HIV-1-specific interleukin-21+ CD4+ T cell responses contribute to durable viral control through the modulation of HIV-specific CD8+ T cell function

Functional defects in cytotoxic CD8(+) T cell responses arise in chronic human viral infections, but the mechanisms involved are not well understood. In mice, CD4 cell-mediated interleukin-21 (IL-21) production is necessary for the maintenance of CD8(+) T cell function and control of persistent viral infections. To investigate the potential role of IL-21 in a chronic human viral infection, we studied the rare subset of HIV-1 controllers, who are able to spontaneously control HIV-1 replication without treatment. HIV-specific triggering of IL-21 by CD4(+) T cells was significantly enriched in these persons (P = 0.0007), while isolated loss of IL-21-secreting CD4(+) T cells was characteristic for subjects with persistent viremia and progressive disease. IL-21 responses were mediated by recognition of discrete epitopes largely in the Gag protein, and expansion of IL-21(+) CD4(+) T cells in acute infection resulted in lower viral set points (P = 0.002). Moreover, IL-21 production by CD4(+) T cells of HIV controllers enhanced perforin production by HIV-1-specific CD8(+) T cells from chronic progressors even in late stages of disease, and HIV-1-specific effector CD8(+) T cells showed an enhanced ability to efficiently inhibit viral replication in vitro after IL-21 binding. These data suggest that HIV-1-specific IL-21(+) CD4(+) T cell responses might contribute to the control of viral replication in humans and are likely to be of great importance for vaccine design.     

Effects of sustained HIV-1 plasma viremia on HIV-1 Gag-specific CD4+ T cell maturation and function

An in vitro proliferative defect has been observed in HIV-1-specific CD4(+) T cells from infected subjects with high-level plasma HIV-1 viremia. To determine the mechanism of this defect, HIV-1 Gag-specific CD4(+) T cells from treated and untreated HIV-1-infected subjects were analyzed for cytokine profile, proliferative capacity, and maturation state. Unexpectedly high frequencies of HIV-1-specific, IL-2-producing CD4(+) T cells were measured in subjects with low or undetectable plasma HIV-1 loads, regardless of treatment status, and IL-2 frequencies correlated inversely with viral loads. IL-2-producing CD4(+) T cells also primarily displayed a central memory (T(Cm); CCR7(+)CD45RA(-)) maturation phenotype, whereas IFN-gamma-producing cells were mostly effector memory (T(Em), CCR7(-)CD45RA(-)). Among Gag-specific, IFN-gamma-producing CD4(+) T cells, higher T(Em) frequencies and lower T(Cm) frequencies were observed in untreated, high viral load subjects than in subjects with low viral loads. The percentage of HIV-1 Gag-specific CD4(+) T(Cm) correlated inversely with HIV-1 viral load and directly with Gag-specific CD4(+) T cell proliferation, whereas the opposite relationships were observed for HIV-1-specific CD4(+) T(Em). These results suggest that HIV-1 viremia skews Gag-specific CD4(+) T cells away from an IL-2-producing T(Cm) phenotype and toward a poorly proliferating T(Em) phenotype, which may limit the effectiveness of the HIV-1-specific immune response.     

CD4+ CD25+ regulatory T cells impair HIV-1-specific CD4 T cell responses by upregulating interleukin-10 production in monocytes

T cell dysfunction in the presence of ongoing antigen exposure is a cardinal feature of chronic viral infections with persistent high viremia, including HIV-1. Although interleukin-10 (IL-10) has been implicated as an important mediator of this T cell dysfunction, the regulation of IL-10 production in chronic HIV-1 infection remains poorly understood. We demonstrated that IL-10 is elevated in the plasma of individuals with chronic HIV-1 infection and that blockade of IL-10 signaling results in a restoration of HIV-1-specific CD4 T cell proliferation, gamma interferon (IFN-γ) secretion, and, to a lesser extent, IL-2 production. Whereas IL-10 blockade leads to restoration of IFN-γ secretion by HIV-1-specific CD4 T cells in all categories of subjects investigated, significant enhancement of IL-2 production and improved proliferation of CD4 T helper cells are restricted to viremic individuals. In peripheral blood mononuclear cells (PBMCs), this IL-10 is produced primarily by CD14(+) monocytes, but its production is tightly controlled by regulatory T cells (Tregs), which produce little IL-10 directly. When Tregs are depleted from PBMCs of viremic individuals, the effect of the IL-10 signaling blockade is abolished and IL-10 production by monocytes decreases, while the production of proinflammatory cytokines, such as tumor necrosis factor alpha (TNF-α), increases. The regulation of IL-10 by Tregs appears to be mediated primarily by contact or paracrine-dependent mechanisms which involve IL-27. This work describes a novel mechanism by which regulatory T cells control IL-10 production and contribute to dysfunctional HIV-1-specific CD4 T cell help in chronic HIV-1 infection and provides a unique mechanistic insight into the role of regulatory T cells in immune exhaustion.     

Infrequent detection of HIV-1-specific, but not cytomegalovirus-specific, CD8(+) T cell responses in young HIV-1-infected infants.

Early potent combination antiretroviral therapies (ART) for HIV-1 infection can preserve or restore immune function, but control of viral replication early in infection may interfere with the development of HIV-1-specific immune responses. Using an IFN-gamma ELISPOT assay, we evaluated the breadth and intensity of HIV-1-specific CD8(+) T cell responses in 17 vertically infected infants who began ART at 1-23 mo of age. CMV-specific responses were also characterized in three infants coinfected with HIV-1 and CMV. Before ART, HIV-1-specific CD8(+) T cell responses were detected in two of 13 (15%) infants <6 mo of age. HIV-1-specific CD8(+) T cells became undetectable in these two infants after the control of viral replication. Intermittent HIV-1-specific responses were noted in six infants who did not experience durable control of viral replication. In contrast, HIV-1-specific responses were detected before ART in four of four infants >6 mo of age and became persistently undetectable in only one child. CMV-specific CD8(+) T cell responses were persistently detected in all HIV-1 and CMV coinfected infants. In conclusion, HIV-1-specific CD8(+) T cell responses were less commonly detected before therapy in young infants than in older infants. Suppression of viral replication appeared to interfere with the development and maintenance of HIV-1-specific CD8(+) T cell responses. The detection of CMV-specific responses in HIV-1 and CMV coinfected infants suggests a selective defect in the generation or maintenance of HIV-1-specific CD8(+) T cell responses. Therapeutic HIV-1 vaccine strategies in young infants may prolong the clinical benefit of ART by expanding the HIV-1-specific CD8(+) T cell pool.     

Galectin-9 and IL-21 Mediate Cross-regulation between Th17 and Treg Cells during Acute Hepatitis C

Loss of CD4 T cell help correlates with virus persistence during acute hepatitis C virus (HCV) infection, but the underlying mechanism(s) remain unknown. We developed a combined proliferation/intracellular cytokine staining assay to monitor expansion of HCV-specific CD4 T cells and helper cytokines expression patterns during acute infections with different outcomes. We demonstrate that acute resolving HCV is characterized by strong Th1/Th17 responses with specific expansion of IL-21-producing CD4 T cells and increased IL-21 levels in plasma. In contrast, viral persistence was associated with lower frequencies of IL-21-producing CD4 T cells, reduced proliferation and increased expression of the inhibitory receptors T cell immunoglobulin and mucin-domain-containing-molecule-3 (Tim-3), programmed death 1 (PD-1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4) on HCV-specific CD8 T cells. Progression to persistent infection was accompanied by increased plasma levels of the Tim-3 ligand Galectin-9 (Gal-9) and expansion of Gal-9 expressing regulatory T cells (Tregs). In vitro supplementation of Tim-3^high HCV-specific CD8 T cells with IL-21 enhanced their proliferation and prevented Gal-9 induced apoptosis. siRNA-mediated knockdown of Gal-9 in Treg cells rescued IL-21 production by HCV-specific CD4 T cells. We propose that failure of CD4 T cell help during acute HCV is partially due to an imbalance between Th17 and Treg cells whereby exhaustion of both CD4 and CD8 T cells through the Tim-3/Gal-9 pathway may be limited by IL-21 producing Th17 cells or enhanced by Gal-9 producing Tregs.     

Virus-specific interleukin-17-producing CD4+ T cells are detectable in early human immunodeficiency virus type 1 infection

T(H)-17 cells have been shown to play a role in bacterial defense, acute inflammation, and autoimmunity. We examined the role of interleukin 17 (IL-17) production in human immunodeficiency virus type 1 (HIV-1) infection. Both HIV-1- and cytomegalovirus (CMV)-specific IL-17-producing CD4(+) T cells were detectable in early HIV-1 infection but were reduced to nondetectable levels in chronic and nonprogressive HIV-1 infection. IL-17-producing CMV-specific cells were not detected in blood from HIV-1-uninfected normal volunteers. Virus-specific T(H)-17 cells could coexpress other cytokines and could express CCR4 or CXCR3. Although the etiology of these cells has yet to be established, we propose that microbial translocation may induce them.     

HIV-1-specific memory CD4+ T cells are phenotypically less mature than cytomegalovirus-specific memory CD4+ T cells

HIV-1-specific CD4(+) T cells are qualitatively dysfunctional in the majority of HIV-1-infected individuals and are thus unable to effectively control viral replication. The current study extensively details the maturational phenotype of memory CD4(+) T cells directed against HIV-1 and CMV. We find that HIV-1-specific CD4(+) T cells are skewed to an early central memory phenotype, whereas CMV-specific CD4(+) T cells generally display a late effector memory phenotype. These differences hold true for both IFN-gamma- and IL-2-producing virus-specific CD4(+) T cells, are present during all disease stages, and persist even after highly active antiretroviral therapy (HAART). In addition, after HAART, HIV-1-specific CD4(+) T cells are enriched for CD27(+)CD28(-)-expressing cells, a rare phenotype, reflecting an early intermediate stage of differentiation. We found no correlation between differentiation phenotype of HIV-1-specific CD4(+) T cells and HIV-1 plasma viral load or HIV-1 disease progression. Surprisingly, HIV-1 viral load affected the maturational phenotype of CMV-specific CD4(+) T cells toward an earlier, less-differentiated state. In summary, our data indicate that the maturational state of HIV-1-specific CD4(+) T cells cannot be a sole explanation for loss of containment of HIV-1. However, HIV-1 replication can affect the phenotype of CD4(+) T cells of other specificities, which might adversely affect their ability to control those pathogens. The role for HIV-1-specific CD4(+) T cells expressing CD27(+)CD28(-) after HAART remains to be determined.     

Shifting hierarchies of interleukin-10-producing T cell populations in the central nervous system during acute and persistent viral encephalomyelitis

Interleukin-10 (IL-10) mRNA is rapidly upregulated in the central nervous system (CNS) following infection with neurotropic coronavirus and remains elevated during persistent infection. Infection of transgenic IL-10/green fluorescent protein (GFP) reporter mice revealed that CNS-infiltrating T cells were the major source of IL-10, with minimal IL-10 production by macrophages and resident microglia. The proportions of IL-10-producing cells were initially similar in CD8(+) and CD4(+) T cells but diminished rapidly in CD8(+) T cells as the virus was controlled. Overall, the majority of IL-10-producing CD8(+) T cells were specific for the immunodominant major histocompatibility complex (MHC) class I epitope. Unlike CD8(+) T cells, a large proportion of CD4(+) T cells within the CNS retained IL-10 production throughout persistence. Furthermore, elevated frequencies of IL-10-producing CD4(+) T cells in the spinal cord supported preferential maintenance of IL-10 production at the site of viral persistence and tissue damage. IL-10 was produced primarily by the CD25(+) CD4(+) T cell subset during acute infection but prevailed in CD25(-) CD4(+) T cells during the transition to persistent infection and thereafter. Overall, these data demonstrate significant fluidity in the T-cell-mediated IL-10 response during viral encephalitis and persistence. While IL-10 production by CD8(+) T cells was limited primarily to the time of acute effector function, CD4(+) T cells continued to produce IL-10 throughout infection. Moreover, a shift from predominant IL-10 production by CD25(+) CD4(+) T cells to CD25(-) CD4(+) T cells suggests that a transition to nonclassical regulatory T cells precedes and is retained during CNS viral persistence.     

Kinetics of the changes of lymphocyte subsets defined by cytokine production at single cell level during highly active antiretroviral therapy for HIV-1 infection

The effects of highly active antiretroviral therapy on cytokine imbalances associated with HIV-1 infection have not been characterized. Using single cell analysis by flow cytometry, we show that a significant recovery in the frequency of IL-2-producing cells was only observed in patients with a sustained control of viral replication and that the overexpanded CD8 T cell population of CD28- IFN-gamma + cells was not significantly reduced after 1 yr of effective therapy. Moreover, a detrimental role of IL-4 is suggested by the association between an enhanced proportion of IL-4-producing cells within the CD4 and particularly the CD8 subset and viral load rebound. Finally, the kinetics of changes of cell subsets assessed for simultaneous production of different cytokines supports the view that cell reconstitution during highly active antiretroviral therapy is initially due to redistribution of terminally differentiated cells, followed by peripheral expansion of less differentiated ones and a late progressive increase of the proportion of functionally defined naive/memory precursor lymphocytes. These data bring new support for the role of cytokine imbalances in AIDS pathogenesis and may be relevant for the definition of immunointervention targets.     

HIV-1 capture and antigen presentation by dendritic cells: enhanced viral capture does not correlate with better T cell activation

During HIV-1 infection, dendritic cells (DC) facilitate dissemination of HIV-1 while trying to trigger adaptive antiviral immune responses. We examined whether increased HIV-1 capture in DC matured with LPS results in more efficient Ag presentation to HIV-1-specific CD4(+) and CD8(+) T cells. To block the DC-mediated trans-infection of HIV-1 and maximize Ag loading, we also evaluated a noninfectious integrase-deficient HIV-1 isolate, HIV(NL4-3ΔIN). We showed that higher viral capture of DC did not guarantee better Ag presentation or T cell activation. Greater HIV(NL4-3) uptake by fully LPS-matured DC resulted in higher viral transmission to target cells but poorer stimulation of HIV-1-specific CD4(+) and CD8(+) T cells. Conversely, maturation of DC with LPS during, but not before, viral loading enhanced both HLA-I and HLA-II HIV-1-derived Ag presentation. In contrast, DC maturation with the clinical-grade mixture consisting of IL-1β, TNF-α, IL-6, and PGE(2) during viral uptake only stimulated HIV-1-specific CD8(+) T cells. Hence, DC maturation state, activation stimulus, and time lag between DC maturation and Ag loading impact HIV-1 capture and virus Ag presentation. Our results demonstrate a dissociation between the capacity to capture HIV-1 and to present viral Ags. Integrase-deficient HIV(NL4-3ΔIN) was also efficiently captured and presented by DC through the HLA-I and HLA-II pathways but in the absence of viral dissemination. HIV(NL4-3ΔIN) seems to be an attractive candidate to be explored. These results provide new insights into DC biology and have implications in the optimization of DC-based immunotherapy against HIV-1 infection.     

Patterns of cytokine production in human immunodeficiency virus type 1 (HIV-1)-specific human CD8+ T cells after stimulation with HIV-1-infected CD4+ T cells

Although human immunodeficiency virus type 1 (HIV-1)-specific CD8+ T cells can produce various cytokines that suppress HIV-1 replication or modulate anti-HIV-1 immunity, the extent to which HIV-1-specific CD8+ T cells produce cytokines when they recognize HIV-1-infected CD4+ T cells in vivo still remains unclear. We first analyzed the abilities of 10 cytotoxic T-lymphocyte (CTL) clones specific for three HIV-1 epitopes to produce gamma interferon, macrophage inflammatory protein 1beta, and tumor necrosis factor alpha after stimulation with epitope peptide-pulsed cells. These CTL clones produced these cytokines in various combinations within the same specificity and among the different specificities, suggesting a functional heterogeneity of HIV-1-specific effector CD8+ T cells in cytokine production. In contrast, the HIV-1-specific CTL clones for the most part produced a single cytokine, without heterogeneity of cytokine production among the clones, after stimulation with HIV-1-infected CD4+ T cells. The loss of heterogeneity in cytokine production may be explained by low surface expression of HLA class I-epitope peptide complexes. Freshly isolated HIV-1-specific CD8+ T cells with an effector/memory or memory phenotype produced much more of the cytokines than the same epitope-specific CTL clones when stimulated with HIV-1-infected CD4+ T cells. Cytokine production from HIV-1-specific memory/effector and memory CD8+ T cells might be a critical event in the eradication of HIV-1 in HIV-1-infected individuals.     

Selective depletion of high-avidity human immunodeficiency virus type 1 (HIV-1)-specific CD8+ T cells after early HIV-1 infection

Human immunodeficiency virus type 1 (HIV-1)-specific CD8+ T cells in early infection are associated with the dramatic decline of peak viremia, whereas their antiviral activity in chronic infection is less apparent. The functional properties accounting for the antiviral activity of HIV-1-specific CD8+ T cells during early infection are unclear. Using cytokine secretion and tetramer decay assays, we demonstrated in intraindividual comparisons that the functional avidity of HIV-1-specific CD8+ T cells was consistently higher in early infection than in chronic infection in the presence of high-level viral replication. This change of HIV-1-specific CD8+ T-cell avidity between early and chronic infections was linked to a substantial switch in the clonotypic composition of epitope-specific CD8+ T cells, resulting from the preferential loss of high-avidity CD8+ T-cell clones. In contrast, the maintenance of the initially recruited clonotypic pattern of HIV-1-specific CD8+ T cells was associated with low-level set point HIV-1 viremia. These data suggest that high-avidity HIV-1-specific CD8+ T-cell clones are recruited during early infection but are subsequently lost in the presence of persistent high-level viral replication.     

Interleukin-15 but not interleukin-7 abrogates vaccine-induced decrease in virus level in simian immunodeficiency virus mac251-infected macaques

The loss of CD4(+) T cells and the impairment of CD8(+) T cell function in HIV infection suggest that pharmacological treatment with IL-7 and IL-15, cytokines that increase the homeostatic proliferation of T cells and improve effector function, may be beneficial. However, these cytokines could also have a detrimental effect in HIV-1-infected individuals, because both cytokines increase HIV replication in vitro. We assessed the impact of IL-7 and IL-15 treatment on viral replication and the immunogenicity of live poxvirus vaccines in SIV(mac251)-infected macaques (Macaca mulatta). Neither cytokine augmented the frequency of vaccine-expanded CD4(+) or CD8(+) memory T cells, clonal recruitment to the SIV-specific CD8(+) T cell pool, or CD8(+) T cell function. Vaccination alone transiently decreased the viral set point following antiretroviral therapy suspension. IL-15 induced massive proliferation of CD4(+) effector T cells and abrogated the ability of vaccination to decrease set point viremia. In contrast, IL-7 neither augmented nor decreased the vaccine effect and was associated with a decrease in TGF-beta expression. These results underscore the importance of testing immunomodulatory approaches in vivo to assess potential risks and benefits for HIV-1-infected individuals.     

The role of CD4+ T cell help and CD40 ligand in the in vitro expansion of HIV-1-specific memory cytotoxic CD8+ T cell responses

CD4(+) T cells have been shown to play a critical role in the maintenance of an effective anti-viral CD8(+) CTL response in murine models. Recent studies have demonstrated that CD4(+) T cells provide help to CTLs through ligation of the CD40 receptor on dendritic cells. The role of CD4(+) T cell help in the expansion of virus-specific CD8(+) memory T cell responses was examined in normal volunteers recently vaccinated to influenza and in HIV-1 infected individuals. In recently vaccinated normal volunteers, CD4(+) T cell help was required for optimal in vitro expansion of influenza-specific CTL responses. Also, CD40 ligand trimer (CD40LT) enhanced CTL responses and was able to completely substitute for CD4(+) T cell help in PBMCs from normal volunteers. In HIV-1 infection, CD4(+) T cell help was required for optimal expansion of HIV-1-specific memory CTL in vitro in 9 of 10 patients. CD40LT could enhance CTL in the absence of CD4(+) T cell help in the majority of patients; however, the degree of enhancement of CTL responses was variable such that, in some patients, CD40LT could not completely substitute for CD4(+) T cell help. In those HIV-1-infected patients who demonstrated poor responses to CD40LT, a dysfunction in circulating CD8(+) memory T cells was demonstrated, which was reversed by the addition of cytokines including IL-2. Finally, it was demonstrated that IL-15 produced by CD40LT-stimulated dendritic cells may be an additional mechanism by which CD40LT induces the expansion of memory CTL in CD4(+) T cell-depleted conditions, where IL-2 is lacking.     

Suppressive CD8+ T cells arise in the absence of CD4 help and compromise control of persistent virus

There is an urgent need to develop novel therapies for controlling chronic virus infections in immunocompromised patients. Disease associated with persistent γ-herpesvirus infection (EBV, human herpesvirus 8) is a significant problem in AIDS patients and transplant recipients, and clinical management of these conditions is difficult. Immune surveillance failure followed by γ-herpesvirus recrudescence can be modeled using murine γ-herpesvirus (MHV)-68 in mice lacking CD4(+) T cells. In contrast with other chronic infections, no obvious defect in the functional capacity of the viral-specific CD8(+) T cell response was detected. We show in this article that adoptive transfer of MHV-68-specific CD8(+) T cells was ineffective at reducing the viral burden. Together, these indicate the potential presence of T cell extrinsic suppressive factors. Indeed, CD4-depleted mice infected with MHV-68 express increased levels of IL-10, a cytokine capable of suppressing the function of both APCs and T cells. CD4-depleted mice developed a population of CD8(+) T cells capable of producing IL-10 that suppressed viral control. Although exhibiting cell surface markers indicative of activation, the IL-10-producing cells expressed increased levels of programmed death-1 but were not enriched in the MHV-68-specific compartment, nor were they uniformly CD44(hi). Therapeutic administration of an IL-10R blocking Ab enhanced control of the recrudescent virus. These data implicate IL-10 as a promising target for the restoration of immune surveillance against chronic γ-herpesvirus infection in immunosuppressed individuals.     

Antigen-independent induction of Tim-3 expression on human T cells by the common γ-chain cytokines IL-2, IL-7, IL-15, and IL-21 is associated with proliferation and is dependent on the phosphoinositide 3-kinase pathway

T cell Ig mucin domain-containing molecule 3 (Tim-3) is a glycoprotein found on the surface of a subset of CD8(+) and Th1 CD4(+) T cells. Elevated expression of Tim-3 on virus-specific T cells during chronic viral infections, such as HIV-1, hepatitis B virus, and hepatitis C virus, positively correlates with viral load. Tim-3(+) cytotoxic T cells are dysfunctional and are unable to secrete effector cytokines, such as IFN-γ and TNF-α. In this study, we examined potential inducers of Tim-3 on primary human T cells. Direct HIV-1 infection of CD4(+) T cells, or LPS, found to be elevated in HIV-1 infection, did not induce Tim-3 on T cells. Tim-3 was induced by the common γ-chain (γc) cytokines IL-2, IL-7, IL-15, and IL-21 but not IL-4, in an Ag-independent manner and was upregulated on primary T cells in response to TCR/CD28 costimulation, as well as γc cytokine stimulation with successive divisions. γc cytokine-induced Tim-3 was found on naive, effector, and memory subsets of T cells. Tim-3(+) primary T cells were more prone to apoptosis, particularly upon treatment with galectin-9, a Tim-3 ligand, after cytokine withdrawal. The upregulation of Tim-3 could be blocked by the addition of a PI3K inhibitor, LY 294002. Thus, Tim-3 can be induced via TCR/CD28 costimulation and/or γc cytokines, likely through the PI3K pathway.     

Greater CD8+ TCR heterogeneity and functional flexibility in HIV-2 compared to HIV-1 infection

Virus-specific CD8(+) T cells are known to play an important role in the control of HIV infection. In this study we investigated whether there may be qualitative differences in the CD8(+) T cell response in HIV-1- and HIV-2-infected individuals that contribute to the relatively efficient control of the latter infection. A molecular comparison of global TCR heterogeneity showed a more oligoclonal pattern of CD8 cells in HIV-1- than HIV-2-infected patients. This was reflected in restricted and conserved TCR usage by CD8(+) T cells recognizing individual HLA-A2- and HLA-B57-restricted viral epitopes in HIV-1, with limited plasticity in their response to amino acid substitutions within these epitopes. The more diverse TCR usage observed for HIV-2-specific CD8(+) T cells was associated with an enhanced potential for CD8 expansion and IFN-gamma production on cross-recognition of variant epitopes. Our data suggest a mechanism that could account for any possible cross-protection that may be mediated by HIV-2-specific CD8(+) T cells against HIV-1 infection. Furthermore, they have implications for HIV vaccine development, demonstrating an association between a polyclonal, virus-specific CD8(+) T cell response and an enhanced capacity to tolerate substitutions within T cell epitopes.     

IL-4-producing CD8+ T cells with a CD62L++(bright) phenotype accumulate in a subgroup of older adults and are associated with the maintenance of intact humoral immunity in old age

An increased production of proinflammatory cytokines occurs in a high percentage of elderly persons and is associated with an impaired humoral immune response. However, high IL-4 production has also been observed in old age. We now demonstrate an IL-4-producing subpopulation of CD8+ T cells in a subgroup of healthy older adults. This T cell subset is substantial in size and has a characteristic phenotype expressing CD45RO, CD28, CD62L, and CD25. IL-4-producing CD8+ T cells produce large amounts of IL-2 but not IFN-gamma or perforin, and these cells do not have a regulatory suppressive effect on other T cells. In vivo IL-4-producing CD8+ T cells can be stably detected over a year. When put into culture they also have a stable cytokine production pattern but fail to produce perforin even in the presence of IL-12. This special T cell type does not occur in persons under the age of 40, but is present in 36% of the persons >60 years of age. In this age group, IL-4-producing CD8+ T cells are more frequent in persons who are still capable of raising a humoral immune response following immunization than in others who fail to produce protective Abs after vaccination. Our results suggest that CD8+ T cells with a CD62L++(bright) phenotype accumulate in a subgroup of older adults. Due to their phenotype that enables them to migrate into lymphoid tissues and to their capacity to produce IL-4, these cells may counterbalance the overproduction of proinflammatory cytokines in old age.     

IL-17 production is dominated by gammadelta T cells rather than CD4 T cells during Mycobacterium tuberculosis infection

IL-17 is a cytokine produced by T cells in response to IL-23. Recent data support a new subset of CD4 Th cells distinct from Th1 or Th2 cells that produce IL-17 and may contribute to inflammation. In this study, we demonstrate that, in naive mice, as well as during Mycobacterium tuberculosis infection, IL-17 production is primarily from gammadelta T cells and other non-CD4(+)CD8(+) cells, rather than CD4 T cells. The production of IL-17 by these cells is stimulated by IL-23 alone, and strongly induced by the cytokines, including IL-23, produced by M. tuberculosis-infected dendritic cells. IL-23 is present in the lungs early in infection and the IL-17-producing cells, such as gammadelta T cells, may represent a central innate protective response to pulmonary infection.