Pathways of memory CD8+ T‐cell development

CD8⁺ T‐cell responses must have at least two components, a replicative cell type that proliferates in the secondary lymphoid tissue and that is responsible for clonal expansion, and cytotoxic cells with effector functions that mediate the resolution of the infection in the peripheral tissues. To confer memory, the response must also generate replication‐competent T cells that persist in the absence of antigen after the primary infection is cleared. The current models of memory differentiation differ in regards to whether or not memory CD8⁺ T cells acquire effector functions during their development. In this review we discuss the existing models for memory development and the consequences that the recent finding that memory CD8⁺ T cells may express granzyme B during their development has for them. We propose that memory CD8⁺ T cells represent a self‐renewing population of T cells that may acquire effector functions but that do not lose the naïve‐like attributes of lymphoid homing, antigen‐independent persistence or the capacity for self‐renewal.     

T‐bet is essential for Th1‐mediated,but not Th17‐mediated,CNS autoimmune disease

T cells that produce both IL‐17 and IFN‐γ, and co‐express ROR‐γt and T‐bet, are often found at sites of autoimmune inflammation. However, it is unknown whether this co‐expression of T‐bet with ROR‐γt is a prerequisite for immunopathology. We show here that T‐bet is not required for the development of Th17‐driven experimental autoimmune encephalomyelitis (EAE). The disease was not impaired in T‐bet^?/? mice and was associated with low IFN‐γ production and elevated IL‐17 production among central nervous system (CNS) infiltrating CD4⁺ T cells. T‐bet^?/? Th17 cells generated in the presence of IL‐6/TGF‐β/IL‐1 and IL‐23 produced GM‐CSF and high levels of IL‐17 and induced disease upon transfer to naïve mice. Unlike their WT counterparts, these T‐bet^?/– Th17 cells did not exhibit an IL‐17→IFN‐γ switch upon reencounter with antigen in the CNS, indicating that this functional change is not critical to disease development. In contrast, T‐bet was absolutely required for the pathogenicity of myelin‐responsive Th1 cells. T‐bet‐deficient Th1 cells failed to accumulate in the CNS upon transfer, despite being able to produce GM‐CSF. Therefore, T‐bet is essential for establishing Th1‐mediated inflammation but is not required to drive IL‐23‐induced GM‐CSF production, or Th17‐mediated autoimmune inflammation.     

Tissue‐resident and memory properties of human T‐cell and NK‐cell subsets

Efficient immune responses to invading pathogens are the result of the complex but coordinated synergy between a variety of cell types from both the innate and adaptive arms of the immune system. While adaptive and innate immune responses are highly complementary, some cells types within these two systems perform similar functions, underscoring the need for redundancy and increased flexibility. In this review, we will discuss the striking shared features of immunological memory and tissue residency recently discovered between T cells, a component of the adaptive immune system, and natural killer (NK) cells, members generally assigned to the innate compartment. Specifically, we will focus on the T‐cell and NK‐cell diversity at the single‐cell level, on the discrete function of specific subsets, and on their anatomical location. Finally, we will discuss the implication of such diversity in the generation of long‐term memory.     

Peripheral CD4+ T‐cell tolerance is induced in vivo by rare antigen‐bearing B cells in follicular,marginal zone,and B‐1 subsets

B cells are efficient APCs when they internalize antigen via BCR‐mediated uptake. Adoptively transferred antigen‐presenting B cells can induce T‐cell tolerance to foreign and self antigens; however, it is unknown whether endogenous B cells presenting self‐peptides interact with naïve T cells and contribute to peripheral T‐cell self‐tolerance. Moreover, the relative abilities of mature B‐cell subsets to induce T‐cell tolerance have not been examined. To address these questions, we created a new mouse model wherein a very small fraction of B cells expresses an antigen transgene that cannot be transferred to other APCs. We limited antigen expression to follicular, marginal zone, or B‐1 B‐cell subsets and found that small numbers of each subset interacted with naïve antigen‐specific T cells. Although antigen expressed by B‐1 B cells induced the most T‐cell division, divided T cells subsequently disappeared from secondary lymphoid tissues. Independent of which B‐cell subset presented antigen, the remaining T cells were rendered hypo‐responsive, and this effect was not associated with Foxp3 expression. Our data show that physiologically relevant proportions of B cells can mediate peripheral T‐cell tolerance, and suggest that the mechanisms of tolerance induction might differ among follicular, marginal zone, and B‐1 B‐cell subsets.     

Tissue‐resident memory T cells: Local guards of the thymus

T‐cell surveillance of nonlymphoid tissues has traditionally been ascribed to recirculating memory T cells that continuously patrol the body. Extending this concept, recent evidence suggests that T cells also exist as nonmigratory memory cells that provide local immune protection in a broad range of peripheral tissues, including barrier locations such as skin and mucosa. In this issue of the European Journal of Immunology, Pircher and colleagues [Eur. J. Immunol. 2013. 43: 2295–2304] demonstrate, for the first time, the existence of such permanently tissue‐resident CD8⁺ memory T (T_RM) cells in a primary lymphoid organ, the thymus. T_RM cells in this location provide potent local immunity, which may help to preserve thymic integrity and normal T‐cell development in the face of infection with thymus‐invading pathogens.     

T‐bet modulates the antibody response and immune protection during murine malaria

CD4⁺ T‐cell subtypes govern the synthesis of different Ab isotypes and other immune functions. The influence of CD4⁺ T‐cell differentiation programs on isotype switching and other aspects of host immunological networks during malaria infection are currently poorly understood. Here, we used Tbx21^?/? mice deficient for T‐bet, a regulator of Th1 CD4⁺ T‐cell differentiation, to examine the effect of Th1 CD4⁺ T cells on the immune protection to nonlethal murine malaria Plasmodium yoelii 17XNL. We found that Tbx21^?/? mice exhibited significantly lower parasite burden that correlated with elevated levels of IgG1, indicating that T‐bet‐dependent Ab isotype switching may be responsible for lower parasite burden. Absence of T‐bet was also associated with a transient but significant loss of T cells during the infection, suggesting that T‐bet may suppress malaria‐induced apoptosis or induce proliferation of T cells. However, Tbx21^?/? mice produced greater numbers of Foxp3⁺CD25⁺ regulatory CD4⁺ T cells, which may contribute to the early contraction of T cells. Lastly, Tbx21^?/? mice exhibited unimpaired production of IFN‐γ by a diverse repertoire of immune cell subsets and a selective expansion of IFN‐γ‐producing T cells. These observations may have implications in malaria vaccine design.     

T‐bet regulates differentiation of forkhead box protein 3+ regulatory T cells in programmed cell death‐1‐deficient mice

Programmed cell death‐1 (PD‐1) plays an important role in peripheral T cell tolerance, but whether or not it affects the differentiation of helper T cell subsets remains elusive. Here we describe the importance of PD‐1 in the control of T helper type 1 (Th1) cell activation and development of forkhead box protein 3 (FoxP3⁺) regulatory T cells (T_regs). PD‐1‐deficient T cell‐specific T‐bet transgenic (P/T) mice showed growth retardation, and the majority died within 10 weeks. P/T mice showed T‐bet over‐expression, increased interferon (IFN)‐γ production by CD4⁺ T cells and significantly low FoxP3⁺ T_reg cell percentage. P/T mice developed systemic inflammation, which was probably induced by augmented Th1 response and low FoxP3⁺ T_reg count. The study identified a unique, previously undescribed role for PD‐1 in Th1 and T_reg differentiation, with potential implication in the development of Th1 cell‐targeted therapy.     

Steady‐state antigen‐expressing dendritic cells terminate CD4+ memory T‐cell responses

CD4⁺ T cells are important effectors of inflammation and tissue destruction in many diseases of immune dysregulation. As memory T cells develop early during the preclinical stages of autoimmune and inflammatory diseases, immunotherapeutic approaches to treatment of these diseases, once established, must include the means to terminate memory T‐cell responses. Traditionally, it has been considered that, due to their terminally differentiated nature, memory T cells are resistant to tolerance induction, although emerging evidence indicates that some immunotherapeutic approaches can terminate memory T‐cell responses. Here, we demonstrate that CD4⁺ memory T‐cell responses can be terminated when cognate antigen is transgenically expressed in steady‐state DC. Transfer of in‐vitro‐generated CD4⁺ memory T cells establishes, in nontransgenic recipients, a stable and readily recalled memory response to cognate antigen. In contrast, upon transfer to mice expressing cognate antigen targeted to DC, memory CD4⁺ T cells undergo a phase of limited proliferation followed by substantial deletion, and recall responses are effectively silenced. This finding is important in understanding how to effectively apply immunotherapy to ongoing T‐cell‐mediated autoimmune and inflammatory diseases.