Jonathan Sprent

Potent and Selective Stimulation of Memory-Phenotype CD8+ T Cells In Vivo by IL-15

Proliferation of memory-phenotype (CD44hi) CD8+ cells induced by infectious agents can be mimicked by injection of type I interferon (IFN I) and by IFN I-inducing agents such as lipopolysaccharide and Poly I:C; such proliferation does not affect naive T cells and appears to be TCR independent. Since IFN I inhibits proliferation in vitro, IFN I-induced proliferation of CD8+ cells in vivo presumably occurs indirectly through production of secondary cytokines, e.g., interleukin-2 (IL-2) or IL-15. We show here that, unlike IL-2, IL-15 closely mimics the effects of IFN I in causing strong and selective stimulation of memory-phenotype CD44hi CD8+ (but not CD4+) cells in vivo; similar specificity applies to purified T cells in vitro and correlates with much higher expression of IL-2Rbeta on CD8+ cells than on CD4+ cells.

Induction of bystander T cell proliferation by viruses and type I interferon in vivo

T cell proliferation in vivo is presumed to reflect a T cell receptor (TCR)-mediated polyclonal response directed to various environmental antigens. However, the massive proliferation of T cells seen in viral infections is suggestive of a bystander reaction driven by cytokines instead of the TCR. In mice, T cell proliferation in viral infections preferentially affected the CD44hi subset of CD8+ cells and was mimicked by injection of polyinosinic-polycytidylic acid [poly(I:C)], an inducer of type I interferon (IFN I), and also by purified IFN I; such proliferation was not associated with up-regulation of CD69 or CD25 expression, which implies that TCR signaling was not involved. IFN I [poly(I:C)]-stimulated CD8+ cells survived for prolonged periods in vivo and displayed the same phenotype as did long-lived antigen-specific CD8+ cells. IFN I also potentiated the clonal expansion and survival of CD8+ cells responding to specific antigen. Production of IFN I may thus play an important role in the generation and maintenance of specific memory.

Extrathymic tolerance of mature T cells: Clonal elimination as a consequence of immunity

The mechanism by which T lymphocytes are tolerized to self or foreign antigens is still controversial. Clonal deletion is the major mechanism of tolerance for immature thymocytes; for mature T cells, tolerance is considered to reflect anergy rather than deletion, and to be a consequence of defective presentation of antigen. This paper documents a novel form of tolerance resulting when mature T cells encounter antigen in immunogenic form. Evidence is presented that exposure of mature T cells to Mlsa antigens in vivo leads to specific tolerance and disappearance of Mlsa-reactive V beta 6+ T cells. Surprisingly, the clonal elimination of V beta 6+ cells is preceded by marked expansion of these cells. Thus, tolerance induction can be the end result of a powerful immune response. These data raise important questions concerning the relationship of tolerance and memory.

IL-7 is critical for homeostatic proliferation and survival of naïve T cells

In T cell-deficient conditions, naïve T cells undergo spontaneous “homeostatic” proliferation in response to contact with self-MHC/peptide ligands. With the aid of an in vitro system, we show here that homeostatic proliferation is also cytokine-dependent. The cytokines IL-4, IL-7, and IL-15 enhanced homeostatic proliferation of naïve T cells in vitro. Of these cytokines, only IL-7 was found to be critical; thus, naïve T cells underwent homeostatic proliferation in IL-4− and IL-15− hosts but proliferated minimally in IL-7− hosts. In addition to homeostatic proliferation, the prolonged survival of naïve T cells requires IL-7. Thus, naïve T cells disappeared gradually over a 1-month period upon adoptive transfer into IL-7− hosts. These findings indicate that naïve T cells depend on IL-7 for survival and homeostatic proliferation.

Homeostasis of Naive and Memory T Cells

The peripheral mature T cell pool is regulated by complex homeostatic mechanisms. Naive T cells are maintained by interleukin-7 (IL-7) and T cell receptor (TCR) signaling from contact with major histocompatibility complex (MHC), which sustain expression of antiapoptotic molecules and allow the cells to survive in interphase. Competition for these ligands declines when T cell numbers are reduced and causes residual naive T cells to proliferate and differentiate into memory-like cells. This memory cell population is thus heterogeneous and comprised of cells derived from responses to both foreign and self-antigens. Typical memory cells are kept alive and induced to divide intermittently by a mixture of IL-7 and IL-15. This review highlights recent advances in how naive and memory T cell homeostasis is regulated.

The Peptide Ligands Mediating Positive Selection in the Thymus Control T Cell Survival and Homeostatic Proliferation in the Periphery

Positive selection to self-MHC/peptide complexes has long been viewed as a device for skewing the T cell repertoire toward recognition of foreign peptides presented by self-MHC molecules. Here, we provide evidence for an alternative possibility, namely, that the self-peptides controlling positive selection in the thymus serve to maintain the longevity of mature T cells in the periphery. Surprisingly, when total T cell numbers are reduced, these self-ligands become overtly stimulatory and cause naive T cells to proliferate and undergo homeostatic expansion.

Interleukin (IL)-15 and IL-7 jointly regulate homeostatic proliferation of memory phenotype CD8+ cells but are not required for memory phenotype CD4+ cells

The overall size and composition of the pool of naive and memory T cells are tightly regulated by homeostatic mechanisms. Recent work has shown that homeostasis of naive T cells is controlled by two factors, self-major histocompatibility complex (MHC)/peptide ligands and a cytokine, interleukin (IL)-7. In particular, contact with these two factors is required for naive CD4+ and CD8+ cells to undergo “homeostatic” proliferation, i.e., proliferation induced as a consequence of severe T cell depletion. In contrast to naive T cells, the factors that drive memory T cells to undergo homeostatic proliferation are poorly understood. To address this issue, purified memory phenotype CD4+ and CD8+ cells from normal mice were adoptively transferred into various gene-knockout mice rendered T cell–deficient by sublethal irradiation. Three findings are reported. First, unlike naive T cells, homeostatic proliferation of memory T cells is largely MHC independent. Second, memory CD8+ cells can utilize either IL-7 or IL-15 to undergo homeostatic proliferation; however, in the absence of both IL-7 and IL-15, homeostatic proliferation fails to occur. Third, unlike memory CD8+ cells, homeostatic proliferation of memory CD4+ cells is independent of IL-7 and IL-15 (also IL-4). Thus, the homeostatic proliferation mechanisms that control memory CD8+ cells and memory CD4+ cells are quite distinct.

Type I interferons act directly on CD8 T cells to allow clonal expansion and memory formation in response to viral infection

T cell expansion and memory formation are generally more effective when elicited by live organisms than by inactivated vaccines. Elucidation of the underlying mechanisms is important for vaccination and therapeutic strategies. We show that the massive expansion of antigen-specific CD8 T cells that occurs in response to viral infection is critically dependent on the direct action of type I interferons (IFN-Is) on CD8 T cells. By examining the response to infection with lymphocytic choriomeningitis virus using IFN-I receptor–deficient (IFN-IR0) and –sufficient CD8 T cells adoptively transferred into normal IFN-IR wild-type hosts, we show that the lack of direct CD8 T cell contact with IFN-I causes >99% reduction in their capacity to expand and generate memory cells. The diminished expansion of IFN-IR0 CD8 T cells was not caused by a defect in proliferation but by poor survival during the antigen-driven proliferation phase. Thus, IFN-IR signaling in CD8 T cells is critical for the generation of effector and memory cells in response to viral infection.

The role of interleukin-2 during homeostasis and activation of the immune system

Interleukin-2 (IL-2) signals influence various lymphocyte subsets during differentiation, immune responses and homeostasis. As discussed in this Review, stimulation with IL-2 is crucial for the maintenance of regulatory T (TReg) cells and for the differentiation of CD4+ T cells into defined effector T cell subsets following antigen-mediated activation. For CD8+ T cells, IL-2 signals optimize both effector T cell generation and differentiation into memory cells. IL-2 is presented in soluble form or bound to dendritic cells and the extracellular matrix. Use of IL-2 — either alone or in complex with particular neutralizing IL-2-specific antibodies — can amplify CD8+ T cell responses or induce the expansion of the TReg cell population, thus favouring either immune stimulation or suppression.

Selective Stimulation of T Cell Subsets with Antibody-Cytokine Immune Complexes

Interleukin-2 (IL-2), which is a growth factor for T lymphocytes, can also sometimes be inhibitory. Thus, the proliferation of CD8+ T cells in vivo is increased after the injection of a monoclonal antibody that is specific for IL-2 (IL-2 mAb), perhaps reflecting the removal of IL-2–dependent CD4+ T regulatory cells (T regs). Instead, we show here that IL-2 mAb augments the proliferation of CD8+ cells in mice simply by increasing the biological activity of preexisting IL-2 through the formation of immune complexes. When coupled with recombinant IL-2, some IL-2/IL-2 mAb complexes cause massive (>100-fold) expansion of CD8+ cells in vivo, whereas others selectively stimulate CD4+ T regs. Thus, different cytokine-antibody complexes can be used to selectively boost or inhibit the immune response.