Th2-like CD8 T cells: their role in protection against infectious diseases

The expression of cytolytic activity and production of interferon gamma (IFN-gamma) by CD8(+) T cells is thought to play a fundamental role in protection against infection by viruses and intracellular parasites. Fran?ois Erard and Graham Le Gros have recently shown that CD8(+) T cells activated in the presence of interleukin 4 (IL-4) can switch development to a CD8(-)CD4(-)Th2-like phenotype that is not cytolytic and that does not produce IFN-gamma. Here they speculate on whether this IL-4-induced switch is used by the host to make a more-effective response against parasite invasion, or i f it is a host mechanism used by the parasite to evade protective CD8(+) T-cell responses.     

Selective activation of extrathymic T cells in the liver by glycyrrhizin

Extrathymic pathways for T cell differentiation were recently demonstrated in the liver, intestine and omentum. In this study, glycyrrhizin (GL), a plant extract was investigated as to its effect on extrathymic T cells in the liver of mice. A new method using anti-LFA-1 mAb in conjunction with anti-TCR or -CD3 mAbs to sensitively identify such extrathymic T cells is included. Single injection and repeated injections of GL increased not only the number of total hepatic MNC but also the proportion of intermediate TCR cells, which are extrathymic T cells uniquely seen in the liver. In contrast to other tested reagents (e.g., lymphotoxin and estrogen) that activated the extrathymic T cells and simultaneously induced profound thymic atrophy, GL did not affect regular T cells in the thymus. The present results suggest that the selective activation of extrathymic T cells in the liver might be intimately related to the clinical effects of GL.     

The role of natural killer T cells and other T cell subsets against infection by the pre-erythrocytic stages of malaria parasites

T cells are critical mediators of immunity to the pre-erythrocytic stages of malaria parasites. In this review, we survey the role of the various T cell subsets in combating the pre-erythrocytic stages; in particular, the role of NK T cells. Moreover, we show how studies using malaria models have revealed a unique behavior of NK T cells, namely the bridging of innate and adaptive immunity.     

CD8+ T effector memory cells protect against liver-stage malaria

Identification of correlates of protection for infectious diseases including malaria is a major challenge and has become one of the main obstacles in developing effective vaccines. We investigated protection against liver-stage malaria conferred by vaccination with adenoviral (Ad) and modified vaccinia Ankara (MVA) vectors expressing pre-erythrocytic malaria Ags. By classifying CD8(+) T cells into effector, effector memory (T(EM)), and central memory subsets using CD62L and CD127 markers, we found striking differences in T cell memory generation. Although MVA induced accelerated central memory T cell generation, which could be efficiently boosted by subsequent Ad administration, it failed to protect against malaria. In contrast, Ad vectors, which permit persistent Ag delivery, elicit a prolonged effector T cell and T(EM) response that requires long intervals for an efficient boost. A preferential T(EM) phenotype was maintained in liver, blood, and spleen after Ad/MVA prime-boost regimens, and animals were protected against malaria sporozoite challenge. Blood CD8(+) T(EM) cells correlated with protection against malaria liver-stage infection, assessed by estimation of number of parasites emerging from the liver into the blood. The protective ability of Ag-specific T(EM) cells was confirmed by transfer experiments into naive recipient mice. Thus, we identify persistent CD8 T(EM) populations as essential for vaccine-induced pre-erythrocytic protection against malaria, a finding that has important implications for vaccine design.     

The role of low avidity T cells in the protection against type 1 diabetes: a modeling investigation

Cytotoxic T lymphocytes (CTLs) play a dominant role in the pathogenesis of autoimmune diabetes, commonly denoted Type 1 Diabetes (T1D). These CTLs (notably CD8⁺ T cells) recognize and kill insulin-secreting pancreatic β cells, reducing their number by ∼90%. The resulting reduction of insulin secretion causes the defective regulation of glucose metabolism, leading to the characteristic symptoms of diabetes. Recognition of β cells as targets by CTLs depends on the interactions between MHC-peptide complexes on the surface of β cells and receptors (TCRs) on T cells. Those CTLs with high affinity TCRs (also called high avidity T cells) cause most of the harm, while those with low affinity TCRs (also called low avidity T cells) play a more mysterious role. Recent experimental evidence suggests that low avidity T cells accumulate as memory T cells during the disease and may be protective in NOD mice (a strain prone to developing T1D), delaying disease progression. It has been hypothesized that such low avidity T cells afford disease protection either by crowding the islets of Langerhans, where β cells reside, or by killing antigen presenting cells (APCs).In this paper, we explore the hypothesized mechanisms for this protective effect in the context of a series of models for (1) the interactions of low and high avidity T cells, (2) the effect of APCs and (3) the feedback from β cell killing to autoantigen-induced T cell proliferation. We analyze properties of these models, noting consistency of predictions with observed behaviour. We then use the models to examine the influence of various treatment strategies on the progression of the disease. The model reveals that progressive accumulation of memory low avidity autoreactive T cells during disease progression makes treatments aimed at expanding these protective T cell types more effective close to, or at the onset of clinical disease. It also provides evidence for the hypothesis that low avidity T cells kill APCs (rather than the alternate hypothesis that they crowd the islets).     

Why T cells of thymic versus extrathymic origin are functionally different

Age-related thymic involution severely impairs immune responsiveness. Strategies to generate T cells extrathymically are therefore being explored with intense interest. We have demonstrated that T cells produced extrathymically were functionally deficient relative to thymus-derived T cells. The main limitation of extrathymic T cells is their undue susceptibility to apoptosis; they thus do not expand properly when confronted with pathogens. Using oncostatin M-transgenic mice, we found that in the absence of lymphopenia, T cells of extrathymic origin constitutively undergo excessive homeostatic proliferation that leads to overproduction of IL-2 and IFN-gamma. IFN-gamma up-regulates Fas and FasL on extrathymic CD8 T cells, thereby leading to their demise by Fas-mediated apoptosis. Moreover, IFN-gamma and probably IL-2 curtail survival of extrathymic CD4 T cells by down-regulating IL-7Ralpha and Bcl-2, and they support a dramatic accumulation of FoxP3(+) T regulatory cells. Additionally, we show that wild-type thymus-derived T cells undergoing homeostatic proliferation in a lymphopenic host shared key features of extrathymic T cells. Our work explains how excessive lymphopenia-independent homeostatic proliferation renders extrathymic T cells functionally defective. Based on previous work and data presented herein, we propose that extrathymic T cells undergo constitutive homeostatic proliferation because they are positively selected by lymph node hemopoietic cells rather than by thymic epithelial cells.     

Commensal-induced regulatory T cells mediate protection against pathogen-stimulated NF-kappaB activation

Host defence against infection requires a range of innate and adaptive immune responses that may lead to tissue damage. Such immune-mediated pathologies can be controlled with appropriate T regulatory (Treg) activity. The aim of the present study was to determine the influence of gut microbiota composition on Treg cellular activity and NF-kappaB activation associated with infection. Mice consumed the commensal microbe Bifidobacterium infantis 35624 followed by infection with Salmonella typhimurium or injection with LPS. In vivo NF-kappaB activation was quantified using biophotonic imaging. CD4+CD25+Foxp3+ T cell phenotypes and cytokine levels were assessed using flow cytometry while CD4+ T cells were isolated using magnetic beads for adoptive transfer to na?ve animals. In vivo imaging revealed profound inhibition of infection and LPS induced NF-kappaB activity that preceded a reduction in S. typhimurium numbers and murine sickness behaviour scores in B. infantis-fed mice. In addition, pro-inflammatory cytokine secretion, T cell proliferation, and dendritic cell co-stimulatory molecule expression were significantly reduced. In contrast, CD4+CD25+Foxp3+ T cell numbers were significantly increased in the mucosa and spleen of mice fed B. infantis. Adoptive transfer of CD4+CD25+ T cells transferred the NF-kappaB inhibitory activity. Consumption of a single commensal micro-organism drives the generation and function of Treg cells which control excessive NF-kappaB activation in vivo. These cellular interactions provide the basis for a more complete understanding of the commensal-host-pathogen trilogue that contribute to host homeostatic mechanisms underpinning protection against aberrant activation of the innate immune system in response to a translocating pathogen or systemic LPS.     

Multipotential acceptance of Peyer's patches in the intestine for both thymus-derived T cells and extrathymic T cells in mice

Peyer's patches (PP) are important inductive sites for the mucosal immune response. It is well known that lymphocytes that migrate into PP are mainly of T-cell lineage from thymus-derived cells (i.e. alphabetaTCR(high) cells). In this study, we further characterized the properties of PP lymphocytes in mice using a mouse model of colitis induced by dextran sulphate sodium (DSS). Although the major site of the inflammation induced by DSS is known to be the large intestine, the small intestine was also damaged. When mice developed DSS-induced colitis, CD3+CD8+B220+ gammadelta T cells increased in PP in the small intestine. These gammadelta T cells, which are not seen in the PP of normal mice, resembled intraepithelial lymphocytes (IEL) in the small intestine in terms of their expression of CD5, CD103 and Thy1.2. In addition, the Vgamma/delta repertoire of these gammadelta T cells was similar to that of gammadelta IEL. When DSS-treated mice were injected with IEL isolated from normal mice, IEL including gammadelta T cells preferentially migrated to PP, raising the possibility that B220+ T cells seen in PP of diseased mice may derive from IEL in the small intestine. Our present study suggests that PP might be able to accept T-cell lineages from intestinal IEL as well as from thymus-derived T cells.     

Correlation of memory T cell responses against TRAP with protection from clinical malaria, and CD4 CD25 high T cells with susceptibility in Kenyans

Background

Immunity to malaria develops naturally in endemic regions, but the protective immune mechanisms are poorly understood. Many vaccination strategies aim to induce T cells against diverse pre-erythrocytic antigens, but correlates of protection in the field have been limited. The objective of this study was to investigate cell-mediated immune correlates of protection in natural malaria. Memory T cells reactive against thrombospondin-related adhesive protein (TRAP) and circumsporozoite (CS) protein, major vaccine candidate antigens, were measured, as were frequencies of CD4⁺ CD25^high T cells, which may suppress immunity, and CD56⁺ NK cells and γδ T cells, which may be effectors or may modulate immunity.

Methodology and Principal Findings

112 healthy volunteers living in rural Kenya were entered in the study. Memory T cells reactive against TRAP and CS were measured using a cultured IFNγ ELISPOT approach, whilst CD4⁺ CD25^high T cells, CD56⁺ NK cells, and γδ T cells were measured by flow cytometry. We found that T cell responses against TRAP were established early in life (<5 years) in contrast to CS, and cultured ELISPOT memory T cell responses did not correlate with ex-vivo IFNγ ELISPOT effector responses. Data was examined for associations with risk of clinical malaria for a period of 300 days. Multivariate logistic analysis incorporating age and CS response showed that cultured memory T cell responses against TRAP were associated with a significantly reduced incidence of malaria (p = 0.028). This was not seen for CS responses. Higher numbers of CD4⁺ CD25^high T cells, potentially regulatory T cells, were associated with a significantly increased risk of clinical malaria (p = 0.039).

Conclusions

These data demonstrate a role for central memory T cells in natural malarial immunity and support current vaccination strategies aimed at inducing durable protective T cell responses against the TRAP antigen. They also suggest that CD4⁺ CD25^high T cells may negatively affect naturally acquired malarial immunity.     

Pathogenic T cells in cerebral malaria

Malaria remains a major global health problem and cerebral malaria (CM) is one of the most serious complications of this disease. Recent years have seen important advances in our understanding of the pathogenesis of cerebral malaria. Parasite sequestration, a hallmark of this syndrome, is thought to be solely responsible for the pathological process. However, this phenomenon cannot explain all aspects of the pathogenesis of CM. The use of an animal model, Plasmodium berghei ANKA in mice, has allowed the identification of specific pathological components of CM. Although multiple pathways may lead to CM, an important role for CD8+ T cells has been clarified. Other cells, including platelets, and mediators such as cytokines also have an important role. In this review we have focused on the role of T cells, and discuss what remains to be studied to understand the pathways by which these cells mediate CM.     

Activation of extrathymic T cells in the liver and reciprocal inactivation of intrathymic T cells by bacterial stimulation.

We recently demonstrated that the liver might be a major site of extrathymic T cell differentiation, including both alpha beta and gamma delta T cells. This extrathymic pathway in the liver, which has a relatively minor role in normal young mice, is activated in mice under bacterial stimulation. In the present study, we investigated how the extrathymic and intrathymic T cell differentiations were mutually related in mice injected intravenously with 10(8) heat-killed Escherichia coli. Three days after stimulation, extrathymic T cells in the liver were observed to be prominently activated in terms of increases in the total number of cells yielded, spontaneous cell proliferation in in vitro culture, and intermediate alpha beta TCR cells. Intermediate alpha beta TCR cells were extrathymic T cells uniquely seen in the liver. However, at the same time intrathymic T cells were profoundly inactivated, showing decreases in the number of thymocytes (more than 90% atrophy), spontaneous cell proliferation, and dull TCR cells with double positive CD4+8+ phenotype. With time, these responses were reversed and normal states were regained. These results suggested that extrathymic and intrathymic T cells are always activated or inactivated in the opposite direction, and that the liver and the thymus are dynamic immune organs. It raises the possibility that the extrathymic T cell differentiation in the liver and the intrathymic T cell differentiation may be reciprocally regulated by certain factors.     

gammadelta T cells in malaria infections

The association of a pronounced gammadelta T-cell response with Plasmodium infections is intriguing. The ability of parasite material to activate gammadelta T cells in vitro, and the localization of these cells in vivo in the red pulp of the spleen, suggests that these cells could play a role in the killing of bloodstage malaria parasites. However, the magnitude, the response and the predominance of inflammatory cytokines secreted by these cells may also indicate a role in the pathology of malaria infections. In this article, Jean Langhorne reveiws the current status of gammadelta T cells in malaria in the context of what is known about the function and specificity of gammadelta T cells in general.     

Adoptive protection against Plasmodium chabaudi adami malaria in athymic nude mice by a cloned T cell line

T cell-dependent, cell-mediated immune mechanisms have been shown to contribute to resistance against malaria. Because the identity of plasmodial Ag responsible for the activation of these protective immune responses remains unknown, a major step in isolating these potential immunizing agents will be the development of adequate screening procedures designed to identify important T cell Ag. This study focused on the isolation of protective T cell clones that may play a pivotal role in this process. A T cell clone designated CTR2.1 and two subclones derived from it adoptively transferred protection to athymic nude mice infected with Plasmodium chabaudi adami, a murine malarial parasite known to be recognized by protective thymus-dependent immune mechanisms. The protective T cell clone displayed a L3T4+, Lyt-2- surface phenotype and secreted both IFN-gamma and IL-2 after stimulation with solubilized parasites in vitro. This is the first report of results demonstrating a cloned T cell line capable of providing adoptive protection against malaria in vivo. More importantly, CTR2.1 and other protective T cell clones may provide for the identification of plasmodial antigenic epitopes recognized by important cell-mediated immune mechanisms during acute malarial infection.     

A retrospective evaluation of the role of T cells in the development of malaria vaccine

Due to the fact that the life cycle of malaria parasites is complex, undergoing both an extracellular and intracellular phases in its host, the human immune system has to mobilize both the humoral and cellular arms of immune responses to fight against this parasitic infection. Whereas humoral immunity is directed toward the extracellular stages which include sporozoites and merozoites, cell-mediated immunity (CMI), in which T cells play a major role, targets hepatic stages - liver stages - of the parasites. In this review, the role of T cells in protective immunity against liver stages of the malaria infection is being re-evaluated. Furthermore, this review intends to address how to translate the findings regarding the role of T cells obtained in experimental systems to actual development of malaria vaccine for humans.     

Development of T lymphocytes at extrathymic sites.

T lymphocytes expressing both CD4 and CD8 are the predominant cell type in the thymic cortex but are extremely rare outside the thymus of normal mice. In this article, we show that if precursor thymocytes (CD4-CD8-) from fetal or adult donors are injected i.v. into irradiated recipients, some of these cells will lodge in lymph nodes and develop into both CD4+CD8+ (double-positive) and CD4+ or CD8+ (single-positive) cells. This phenomenon also occurred in thymectomized recipients, strongly suggesting it is genuine extrathymic development. Prethymic precursors (e.g., fetal liver), were unable to use the lymph node for T cell development, without thymic processing. The data suggest that given unusual circumstances (irradiation or thymectomy and availability of appropriate precursors), the lymph nodes can support T cell development.     

On the pathogenic role of brain-sequestered alphabeta CD8+ T cells in experimental cerebral malaria

Cerebral malaria (CM) develops in a small proportion of persons infected with Plasmodium falciparum and accounts for a substantial proportion of the mortality due to this parasite. The actual pathogenic mechanisms are still poorly understood, and in humans investigations of experimental CM are unethical. Using an established Plasmodium berghei-mouse CM model, we have investigated the role of host immune cells at the pathological site, the brain. We report in this study the detailed quantification and characterization of cells, which migrated and sequestered to the brain of mice with CM. We demonstrated that CD8(+) alphabeta T cells, which sequester in the brain at the time when neurological symptoms appear, were responsible for CM mortality. These observations suggest a mechanism which unifies disparate observations in humans.