Regulatory CD4 T cells control the size of the peripheral activated/memory CD4 T cell compartment

The mechanisms leading to stable T cell numbers in the periphery of a healthy animal are, to date, not well understood. We followed the expansion of CD45RBhigh (naive) and CD45RBlow (activated/memory) CD4 T cells transferred from normal mice into syngeneic Rag-20/0 recipients and the dynamics of peripheral reconstitution when both populations were coinjected. Naive cells acquired an activated phenotype and showed a high proliferative capacity that was dependent on the environment in which the recipients were kept (specific pathogen-free vs conventional housing conditions), the age of the recipients, and the presence of CD45RBlow T cells in the injected cohort. CD45RBlow CD4 T cells protected the host from CD45RBhigh CD4 T cell-induced inflammatory bowel disease and showed a limited degree of expansion. CD45RBlow CD4 T cells isolated from GF mice also showed the ability to prevent inflammatory bowel disease, indicating that at least part of the natural regulatory T cells are self-reactive. The results indicate that 1) peripheral T cell expansion in lymphocyte-deficient recipients represent classical immune responses, which are mainly promoted by exogenous Ags and 2) natural regulatory T cells control the size of the activated/memory peripheral CD4 T cell compartment.     

Induction of CD4+ T cell alloantigen-specific hyporesponsiveness by IL-10 and TGF-beta.

Induction and maintenance of Ag-specific tolerance are pivotal for immune homeostasis, prevention of autoimmune disorders, and the goal of transplantation. Recent studies suggest that certain cytokines, notably IL-10 and TGF-beta, may play a role in down-regulating immune functions. To further examine the role of cytokines in Ag-specific hyporesponsiveness, murine CD4+ T cells were exposed ex vivo to alloantigen-bearing stimulators in the presence of exogenous IL-10 and/or TGF-beta. Primary but not secondary alloantigen proliferative responses were inhibited by IL-10 alone. However, the combined addition of IL-10 + TGF-beta markedly induced alloantigen hyporesponsiveness in both primary and secondary MLR cultures. Alloantigen-specific hyporesponsiveness was observed also under conditions in which nominal Ag responses were intact. In adoptive transfer experiments, IL-10 + TGF-beta-treated CD4+ T cells, but not T cells treated with either cytokine alone, were markedly impaired in inducing graft-vs-host disease alloresponses to MHC class II disparate recipients. These data provide the first formal evidence that IL-10 and TGF-beta have at least an additive effect in inducing alloantigen-specific tolerance, and that in vitro cytokines can be exploited to suppress CD4+ T cell-mediated Ag-specific responses in vivo.     

Cutting edge: CD4+ T cell control of CD8+ T cell reactivity to a model tumor antigen

Neoantigens resulting from the inherent genomic instability of tumor cells generally do not trigger immune recognition. Similarly, transfection of tumors with model Ags often fails to elicit CD8+ T cell responses or alter a tumor's growth rate or lethality. We report here that the adoptive transfer of activated Th1-type CD4+ T cells specific for a model tumor Ag results in the de novo generation of CD8+ T cells with specificity to that Ag and concomitant tumor destruction. The anti-tumor effects of the CD4+ T cells required the presence of both MHC class I and class II on host cells, as evidenced by experiments in knockout mice, suggesting that CD4+ T cells enhanced the ability of host APC to activate endogenous CD8+ T cells. These results indicate that the apparent inability of tumor cells expressing highly immunogenic epitopes to activate tumor-specific CD8+ T cells can be altered by activated CD4+ T cells.     

Dynamic differentiation of activated human peripheral blood CD8+ and CD4+ effector memory T cells

Two functionally different memory T cell subsets were originally defined based on their different CCR7 expression profile, but the lineage relationship between these subsets referred to as central memory T cells (T(CM)) and effector memory T cells (T(EM)), is not resolved. A prevalent model proposes a linear progressive differentiation from T(CM) to T(EM). Our results demonstrate that on activation, human CCR7-CD62L- peripheral blood CD8+ and CD4+ T(EM) cells exhibit a dynamic differentiation, involving transient as well as stable changes to T(CM) phenotype and properties. Whereas the larger fraction of T(EM) cells increases expression of effector molecules, such as perforin or IFN-gamma, a smaller fraction first acquires CCR7 expression. We demonstrate that this acquisition of lymph node homing potential is associated with strong proliferation similar to that of activated T(CM) cells. After proliferation, most of these cells lose CCR7 expression again and acquire effector functions (e.g., perforin production). A small proportion (approximately 6%), however, maintain phenotypic and functional T(CM) properties over a long time interval. These results suggest that T(EM) cells provide immediate effector function by a fraction of cells as well as self-renewal by others through up-regulation of CCR7 followed by either secondary peripheral effector function or long term maintenance of T(CM)-like properties.     

CTLA-4 and CD4+ CD25+ regulatory T cells inhibit protective immunity to filarial parasites in vivo

The T cell coinhibitory receptor CTLA-4 has been implicated in the down-regulation of T cell function that is a quintessential feature of chronic human filarial infections. In a laboratory model of filariasis, Litomosoides sigmodontis infection of susceptible BALB/c mice, we have previously shown that susceptibility is linked both to a CD4+ CD25+ regulatory T (Treg) cell response, and to the development of hyporesponsive CD4+ T cells at the infection site, the pleural cavity. We now provide evidence that L. sigmodontis infection drives the proliferation and activation of CD4+ Foxp3+ Treg cells in vivo, demonstrated by increased uptake of BrdU and increased expression of CTLA-4, Foxp3, GITR, and CD25 compared with naive controls. The greatest increases in CTLA-4 expression were, however, seen in the CD4+ Foxp3- effector T cell population which contained 78% of all CD4+ CTLA-4+ cells in the pleural cavity. Depletion of CD25+ cells from the pleural CD4+ T cell population did not increase their Ag-specific proliferative response in vitro, suggesting that their hyporesponsive phenotype is not directly mediated by CD4+ CD25+ Treg cells. Once infection had established, killing of adult parasites could be enhanced by neutralization of CTLA-4 in vivo, but only if performed in combination with the depletion of CD25+ Treg cells. This work suggests that during filarial infection CTLA-4 coinhibition and CD4+ CD25+ Treg cells form complementary components of immune regulation that inhibit protective immunity in vivo.     

Toll-like receptor ligands directly promote activated CD4+ T cell survival

Toll-like receptor (TLR) engagement by pathogen-associated molecular patterns (PAMPs) is an important mechanism for optimal cellular immune responses. APC TLR engagement indirectly enhances activated CD4(+) T cell proliferation, differentiation, and survival by promoting the up-regulation of costimulatory molecules and the secretion of proinflammatory cytokines. However, TLRs are also expressed on CD4(+) T cells, suggesting that PAMPs may also act directly on activated CD4(+) T cells to mediate functional responses. In this study, we show that activated mouse CD4(+) T cells express TLR-3 and TLR-9 but not TLR-2 and TLR-4. Treatment of highly purified activated CD4(+) T cells with the dsRNA synthetic analog poly(I:C) and CpG oligodeoxynucleotides (CpG DNA), respective ligands for TLR-3 and TLR-9, directly enhanced their survival without augmenting proliferation. In contrast, peptidoglycan and LPS, respective ligands for TLR-2 and TLR-4 had no effect. Enhanced survival mediated by either poly(I:C) or CpG DNA required NF-kappaB activation and was associated with Bcl-x(L) up-regulation. However, only CpG DNA, but not poly(I:C)-mediated effects on activated CD4(+) T cells required the TLR/IL-1R domain containing adaptor molecule myeloid differentiation factor 88. Collectively, our results demonstrate that PAMPs can directly promote activated CD4(+) T cell survival, suggesting that TLRs on T cells can directly modulate adaptive immune responses.     

CD4+CD25+调节性T细胞的作用机制及临床应用

免疫应答通常是机体对各种异源物质的重要防御机制.但有些免疫应答会造成机体的损伤.近来,大量研究发现免疫系统内存在一类CD4 CD25 调节性T淋巴(CD4 CD25 regulatory T cell,CD4 CD25 TReg),在阻止大量免疫介导的疾病中起重要作用.该文从自身免疫耐受、维持T细胞自稳态、肿瘤免疫等方面介绍这类细胞的免疫调节作用.     

CD31 is required on CD4+ T cells to promote T cell survival during Salmonella infection

Hematopoietic cells constitutively express CD31/PECAM1, a signaling adhesion receptor associated with controlling responses to inflammatory stimuli. Although expressed on CD4(+) T cells, its function on these cells is unclear. To address this, we have used a model of systemic Salmonella infection that induces high levels of T cell activation and depends on CD4(+) T cells for resolution. Infection of CD31-deficient (CD31KO) mice demonstrates that these mice fail to control infection effectively. During infection, CD31KO mice have diminished numbers of total CD4(+) T cells and IFN-γ-secreting Th1 cells. This is despite a higher proportion of CD31KO CD4(+) T cells exhibiting an activated phenotype and an undiminished capacity to prime normally and polarize to Th1. Reduced numbers of T cells reflected the increased propensity of naive and activated CD31KO T cells to undergo apoptosis postinfection compared with wild-type T cells. Using adoptive transfer experiments, we show that loss of CD31 on CD4(+) T cells alone is sufficient to account for the defective CD31KO T cell accumulation. These data are consistent with CD31 helping to control T cell activation, because in its absence, T cells have a greater propensity to become activated, resulting in increased susceptibility to become apoptotic. The impact of CD31 loss on T cell homeostasis becomes most pronounced during severe, inflammatory, and immunological stresses such as those caused by systemic Salmonella infection. This identifies a novel role for CD31 in regulating CD4 T cell homeostasis.     

Organ-specific CD4+ T cell response during Listeria monocytogenes infection

The immune response against the intracellular bacterium Listeria monocytogenes involves both CD4(+) and CD8(+) T cells. We used the MHC class II-presented peptide listeriolysin(189-201) to characterize the organ-specific CD4(+) T cell response during infection. Systemic listeriosis resulted in a strong peptide-specific CD4(+) T cell response with frequencies of 1/100 and 1/30 CD4(+) splenocytes at the peak of primary and secondary response, respectively. This response was not restricted to lymphoid organs, because we detected specific CD4(+) T cells in all tissues analyzed. However, the tissue distribution of the T cell response was dependent on the route of infection. After i.v. infection, the strongest CD4(+) T cell response and the highest levels of memory cells were observed in spleen and liver, the major sites of L. monocytogenes replication. After oral infection, we detected a strong response in the liver, the lamina propria, and the intestinal epithelium. These tissues also harbored the highest frequencies of listeriolysin(189-201)-specific CD4(+) memory T cells 5-8 wk post oral infection. Our results show that kinetics and magnitude of the CD4(+) T cell response and the accumulation of CD4(+) memory T cells depend on the route of infection and are regulated in a tissue-specific way.     

Enumeration and functional evaluation of virus-specific CD4+ and CD8+ T cells in lymphoid and peripheral sites of coxsackievirus B3 infection

Previous studies have suggested that coxsackievirus B (CVB) activates CD8⁺ T cells in vivo, but the extent of this activation and the antigen specificity of the CD8⁺ T cells remain uncertain. Furthermore, CVB-induced CD4⁺ T-cell responses have not been carefully investigated. Herein, we evaluate CD8⁺ and CD4⁺ T-cell responses both in a secondary lymphoid organ (spleen) and in peripheral tissues (heart and pancreas), using a recombinant CVB3 (rCVB3.6) that encodes well-characterized CD8⁺ and CD4⁺ T-cell epitopes. Despite reaching high levels in vivo, rCVB3.6 failed to trigger a marked expansion of CD8⁺ or CD4⁺ T cells, and T-cell activation was surprisingly limited. Furthermore, epitope-specific effector functions could not be detected using highly sensitive in vivo and ex vivo assays. Moreover, major histocompatibility complex (MHC) class I tetramer analysis indicated that our inability to detect CVB3-specific CD8⁺ T-cell responses could not be explained by the cells being dysfunctional. In contrast to naïve T cells, epitope-specific memory CD8⁺ and CD4⁺ T cells proliferated markedly, indicating that both of the rCVB3.6-encoded epitopes were presented by their respective MHC molecules in vivo. These data are consistent with the observation that several CVB3 proteins can limit the presentation of viral epitopes on the surface of infected cells and suggest that the level of MHC/peptide complex is sufficient to trigger memory but not naïve T cells. Finally, our findings have implications for the biological significance of cross-priming, a process thought by some to be important for the induction of antiviral CD8⁺ T-cell responses.Coxsackieviruses are members of the picornavirus family and enterovirus genus, which includes type A and B coxsackieviruses, polioviruses, echoviruses, and other unclassified enteroviruses. Although the majority of type B coxsackievirus (CVB) infections in humans are subclinical or cause relatively mild disease (including rash, myalgia, or upper respiratory complications), CVB are important human pathogens, and a substantial proportion of infections can lead to severe—even lethal—acute and chronic diseases. In particular, CVB is the most common infectious cause of myocarditis, which can lead to dilated cardiomyopathy and cardiac failure (38, 44, 45). CVB also targets cells of the central nervous system and the pancreas, frequently leading to aseptic meningitis and pancreatitis (7, 12, 33, 35, 40). Overall, CVB infection can cause considerable morbidity and mortality, particularly in newborns and in young or immunocompromised individuals (35, 52).The murine model of CVB3 infection is a valuable system for studying CVB pathogenesis and immunity, as mice infected with CVB develop diseases similar to those observed in humans (52, 53). Intraperitoneal inoculation of adult C57BL/6 mice with CVB3 results in systemic acute infection; viremia peaks on day 2 to 3 postinfection (p.i.), and infectious virus is cleared by 2 weeks p.i. (33, 34). Control of CVB3 infection depends on both cell-mediated and humoral components of the immune response. Agammaglobulinemic individuals are particularly susceptible to CVB3-associated encephalitis (15, 18), and mice lacking B cells develop a chronic infection and remain viremic for at least 2 months; viremia can be alleviated by the adoptive transfer of B cells from CVB3-immune wild-type mice (34). CD8⁺ T cells also play an important role in controlling virus replication. T cells are present in the inflammatory infiltrates associated with myocarditis and pancreatitis (17, 20, 41), and CD8⁺ T-cell depletion of CVB3-infected mice simultaneously increases viral titers and reduces myocarditis, suggesting that T-cell-mediated protection is associated with elevated immunopathology (17). This immunopathology can be uncoupled from antiviral efficacy; mice lacking perforin control cardiac infection just as well as wild-type mice but show markedly diminished myocarditis (14).Many—probably most—acute viral infections trigger extensive CD8⁺ T-cell activation and division; these responses can readily be detected directly ex vivo, without any need for extensive restimulation. The convincing evidence that CD8⁺ T cells can contribute to control of CVB3 in mice, together with the fact that CVB3 replicates to high titers in many mouse tissues, led us to surmise that CVB3—like most other viruses—would induce readily detectable CD8⁺ T-cell responses in mice. Indeed, early studies had identified cytolytic T-cell activity in CVB3-infected mice, although the precise antigen specificity of the cells was unknown (16, 21, 22). Subsequent elegant work showed that synthetic peptides representing CVB3 VP1 sequences could drive in vitro T-cell proliferation, but neither the phenotype of the proliferating T cells (CD4⁺ or CD8⁺) nor the precise epitope specificity was determined (19). Therefore, we undertook a preliminary analysis of epitope-specific CD8⁺ T-cell responses against CVB3; contrary to our expectations, we found that CVB3-induced epitope-specific CD8⁺ T-cell responses were difficult to detect (42). However, those studies were incomplete: they relied on ex vivo detection methods of rather limited sensitivity, and they were limited to cells from the spleen. Furthermore, those studies focused only on CD8⁺ T cells, and it is clear that regulation of antiviral CD8⁺ T cells differs from that of CD4⁺ T cells. Therefore, herein we have extended our previous analysis in five ways: first, we evaluate general T-cell activation in CVB3-infected mice; second, we use more sensitive in vivo approaches to detect epitope-specific T-cell responses; third, we investigate the possibility that the virus induces the expansion of dysfunctional T cells; fourth, we extend our analyses of CVB3 epitope-specific T-cell responses to major targets of infection, such as the heart, where CD8⁺ T cells are present in the virus-induced infiltrate; and, fifth, we investigate CD4⁺ T-cell responses induced by CVB3. Our studies employ a new recombinant CVB3 (rCVB3) that encodes both a CD8 and CD4 T-cell epitope derived from lymphocytic choriomeningitis virus (LCMV). Our data are not only relevant to understanding the T-cell responses induced by coxsackievirus in particular but also have broader implications for the mechanism(s) by which CD4⁺ and CD8⁺ T cells are induced by viruses in general.     

CD4+ T cell responses in the immune control against latent infection by Epstein-Barr virus

The human gamma-herpesvirus Epstein-Barr virus establishes latent, life-long infection in more than 95% of the human adult population. Despite its growth transforming capacity, most carriers control EBV associated malignancies efficiently and remain free of EBV+ tumors. It is commonly accepted that lymphoblastoid cells, expressing all EBV latent antigens, are targeted by the immune system and cause tumors only in immune-suppressed individuals. However, immune control of EBV associated malignancies which express only three or one EBV latent antigen is less obvious. Recent studies have addressed the pattern of EBV latent infection in healthy EBV carriers and the identity of EBV derived target antigens for CD4+ T cells. The results suggest that immune surveillance also extends to tumors, which have down-regulated most EBV latent antigens and therefore escape EBV specific immune recognition at least in part. EBV specific immunity that targets these tumors in healthy EBV carriers seems to fail specifically during the development of Hodgkin's disease, nasopharyngeal carcinoma and Burkitt's lymphoma. These three EBV+ tumors appear to subdue EBV immunity against the remaining EBV latent antigens in different ways or profit from the effect of other pathogens on EBV specific immune responses, when they develop in otherwise immune competent individuals. While immune control and immune escape of these so-called spontaneously arising EBV associated malignancies is just beginning to be understood, immune control of persisting EBV infection can serve as a model for tumor immune surveillance in general.     

Identification of an interleukin 17F/17A heterodimer in activated human CD4+ T cells

IL-17F and IL-17A are members of the IL-17 pro-inflammatory cytokine family. IL-17A has been implicated in the pathogenesis of autoimmune diseases. IL-17F is a disulfide-linked dimer that contains a cysteine-knot motif. We hypothesized that IL-17F and IL-17A could form a heterodimer due to their sequence homology and overlapping pattern of expression. We evaluated the structure of recombinant IL-17F and IL-17A proteins, as well as that of natural IL-17F and IL-17A derived from activated human CD4+ T cells, by enzyme-linked immunosorbent assay, immunoprecipitation followed by Western blotting, and mass spectrometry. We find that both IL-17F and IL-17A can form both homodimeric and heterodimeric proteins when expressed in a recombinant system, and that all forms of the recombinant proteins have in vitro functional activity. Furthermore, we find that in addition to the homodimers of IL-17F and IL-17A, activated human CD4+ T cells also produce the IL-17F/IL-17A heterodimer. These data suggest that the IL-17F/IL-17A heterodimer may contribute to the T cell-mediated immune responses.     

Antigen nonspecific suppression of T cell responses by activated stimulation-refractory CD4+ T cells

Several classes of anergic T cells are capable of suppressing naive T cell proliferation and thereby limiting immune responses. Activated T cells, although not anergic, are transiently refractory to restimulation with Ag. We examine in this study whether activated refractory murine T cells can also suppress naive T cell responses. We find that they can, and that they exhibit many of the suppressive properties of anergic T cells. The activated cells strongly diminish Ag-mediated T cell proliferation, an activity that correlates with their refractory period. Suppression is independent of APC numbers and requires cell contact or proximity. Naive T cells stimulated in the presence of activated refractory cells up-regulate CD25 and CD69, but fail to produce IL-2. The addition of IL-2 to culture medium, however, does not prevent the suppression, which is therefore not solely due to the absence of this growth factor. Persistence of the suppressor cells is also not essential. T cells stimulated in their presence and then isolated from them and cultured do not divide. The suppressive cells, however, do not confer a refractory or anergic state on the target T lymphocytes, which can fully respond to antigenic stimulation if removed from the suppressors. Our results therefore provide evidence that activated T cells act as transient suppressor cells, severely constraining bystander T cell stimulation and thereby restricting their response. These results have potentially broad implications for the development and regulation of immune responses.     

Sonic hedgehog promotes cell cycle progression in activated peripheral CD4(+) T lymphocytes

Sonic hedgehog (Shh) signaling is important in the growth and differentiation of many cell types and recently has been reported to play a role in T cell development in the thymus. This prompted us to investigate whether or not Shh contributes to the clonal expansion of peripheral CD4(+) T cells. In this study, we demonstrate that Shh and other components of the signaling pathway patched, smoothened, and Gli1 (glioma-associated oncogene) are expressed in peripheral CD4(+) T cells. The addition of the biologically active amino-terminal Shh peptide had no effect on resting CD4(+) T cells, but significantly enhanced proliferation of anti-CD3/28 Ab-activated CD4(+) T cells. This was not due to antiapoptotic effects, but by promoting entry of T cells into the S-G(2) proliferative phase of the cell cycle. Neutralizing anti-Shh Ab reduced T cell proliferation by inhibiting cell transition into the S-G(2) phase, suggesting that endogenously produced Shh plays a physiological role in the clonal expansion of T cells. Furthermore, we have observed a significant up-regulation of Shh and Gli1 (glioma-associated oncogene) mRNA in activated CD4(+) T cells with or without addition of exogenous Shh, which corresponds with maximal CD4(+) T cell proliferation, whereas bcl-2 was only up-regulated in activated cells in the presence of Shh. Our findings suggest that endogenously produced Shh may play a role in sustaining normal CD4(+) T cell proliferation and exogenously added Shh enhances this response.     

CD4+CD8+ T cells represent a significant portion of the anti-HIV T cell response to acute HIV infection

Previous studies have revealed that HIV-infected individuals possess circulating CD4(+)CD8(+) double-positive (DP) T cells specific for HIV Ags. In the present study, we analyzed the proliferation and functional profile of circulating DP T cells from 30 acutely HIV-infected individuals and 10 chronically HIV-infected viral controllers. The acutely infected group had DP T cells that showed more proliferative capability and multifunctionality than did both their CD4(+) and CD8(+) T cells. DP T cells were found to exhibit greater proliferation and higher multifunctionality compared with CD4 T cells in the viral controller group. The DP T cell response represented 16% of the total anti-HIV proliferative response and >70% of the anti-HIV multifunctional response in the acutely infected subjects. Proliferating DP T cells of the acutely infected subjects responded to all HIV Ag pools with equal magnitude. Conversely, the multifunctional response was focused on the pool representing Nef, Rev, Tat, VPR, and VPU. Meanwhile, the controllers' DP T cells focused on Gag and the Nef, Rev, Tat, VPR, and VPU pool for both their proliferative and multifunctional responses. Finally, we show that the presence of proliferating DP T cells following all HIV Ag stimulations is well correlated with proliferating CD4 T cells whereas multifunctionality appears to be largely independent of multifunctionality in other T cell compartments. Therefore, DP T cells represent a highly reactive cell population during acute HIV infection, which responds independently from the traditional T cell compartments.     

In vivo CD86 blockade inhibits CD4+ T cell activation, whereas CD80 blockade potentiates CD8+ T cell activation and CTL effector function

To address whether a functional dichotomy exists between CD80 and CD86 in naive T cell activation in vivo, we administered anti-CD80 or CD86 blocking mAb alone or in combination to mice with parent-into-F(1) graft-vs-host disease (GVHD). In this model, the injection of naive parental T cells into unirradiated F(1) mice results in either a Th1 cytokine-driven, cell-mediated immune response (acute GVHD) or a Th2 cytokine-driven, Ab-mediated response (chronic GVHD) in the same F(1) recipient. Combined CD80/CD86 blockade beginning at the time of donor cell transfer mimicked previous results seen with CTLA4Ig and completely abrogated either acute or chronic GVHD by preventing the activation and maturation of donor CD4(+) T cells as measured by a block in acquisition of memory marker phenotype and cytokine production. Similar results were seen with selective CD86 blockade; however, the degree of CD4 inhibition was always less than that seen with combined CD80/CD86 blockade. A more striking effect was seen with selective CD80 blockade in that chronic GVHD was converted to acute GVHD. This effect was associated with the induction of Th1 cytokine production, donor CD8(+) T cell activation, and development of antihost CTL. The similarity of this effect to that reported for selective CTLA4 blockade suggests that CD80 is a critical ligand for CTLA4 in mediating the down-regulation of Th1 responses and CD8(+) T cell activation. In contrast, CD86 is critical for the activation of naive CD4(+) T cells in either a Th1 or a Th2 cytokine-mediated response.     

Limited CD4+ T cell proliferation leads to preservation of CD4+ T cell counts in SIV-infected sooty mangabeys

Human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infections result in chronic virus replication and progressive depletion of CD4+ T cells, leading to immunodeficiency and death. In contrast, ‘natural hosts’ of SIV experience persistent infection with high virus replication but no severe CD4+ T cell depletion, and remain AIDS-free. One important difference between pathogenic and non-pathogenic infections is the level of activation and proliferation of CD4+ T cells. We analysed the relationship between CD4+ T cell number and proliferation in HIV, pathogenic SIV in macaques, and non-pathogenic SIV in sooty mangabeys (SMs) and mandrills. We found that CD4+ T cell proliferation was negatively correlated with CD4+ T cell number, suggesting that animals respond to the loss of CD4+ T cells by increasing the proliferation of remaining cells. However, the level of proliferation seen in pathogenic infections (SIV in rhesus macaques and HIV) was much greater than in non-pathogenic infections (SMs and mandrills). We then used a modelling approach to understand how the host proliferative response to CD4+ T cell depletion may impact the outcome of infection. This modelling demonstrates that the rapid proliferation of CD4+ T cells in humans and macaques associated with low CD4+ T cell levels can act to ‘fuel the fire’ of infection by providing more proliferating cells for infection. Natural host species, on the other hand, have limited proliferation of CD4+ T cells at low CD4+ T cell levels, which allows them to restrict the number of proliferating cells susceptible to infection.     

CD4+CD25+ regulatory T cells in HIV infection

The immune system faces the difficult task of discerning between foreign, potentially pathogen-derived antigens and self-antigens. Several mechanisms, including deletion of self-reactive T cells in the thymus, have been shown to contribute to the acceptance of self-antigens and the reciprocal reactivity to foreign antigens. Over the last decade it has become increasingly clear that CD4(+)CD25(+) T(Reg) cells are crucial for maintenance of T cell tolerance to self-antigens in the periphery, and to avoid development of autoimmune disorders. Recently, evidence has also emerged that demonstrates that CD4(+)CD25(+) T(Reg) cells can also suppress T cell responses to foreign pathogens, including viruses such as HIV. In this article we review the current knowledge and potential role of CD4(+)CD25(+) T(Reg) cells in HIV infection.