Antiviral CD4+ memory T cells are IL-15 dependent

Survival and intermittent proliferation of memory CD4+ and CD8+ T cells appear to be controlled by different homeostatic mechanisms. In particular, contact with interleukin (IL)-15 has a decisive influence on memory CD8+ cells, but not memory CD4+ cells. Past studies of memory CD4+ cells have relied heavily on the use of naturally occurring memory phenotype (MP) cells as a surrogate for antigen (Ag)-specific memory cells. However, we show here that MP CD4+ cells contain a prominent subset of rapidly proliferating major histocompatibility complex (MHC) II–dependent cells. In contrast, Ag-specific memory CD4 cells have a slow turnover rate and are MHC II independent. In irradiated hosts, these latter cells ignore IL-15 and expand in response to the elevated levels of IL-7 in the lymphopenic hosts. In contrast, in normal nonlymphopenic hosts where IL-7 levels are low, memory CD4 cells are heavily dependent on IL-15. Significantly, memory CD4+ responsiveness to endogenous IL-15 reflects marked competition from other cells, especially CD8+ and natural killer cells, and increases considerably after removal of these cells. Therefore, under normal physiological conditions, homeostasis of CD8+ and CD4+ memory cells is quite similar and involves IL-15 and IL-7

The aged lymphoid tissue environment fails to support naive T cell homeostasis.

Aging is associated with a gradual loss of naive T cells and a reciprocal increase in the proportion of memory T cells. While reduced thymic output is important, age-dependent changes in factors supporting naive T cells homeostasis may also be involved. Indeed, we noted a dramatic decrease in the ability of aged mice to support survival and homeostatic proliferation of naive T cells. The defect was not due to a reduction in IL-7 expression, but from a combination of changes in the secondary lymphoid environment that impaired naive T cell entry and access to key survival factors. We observed an age-related shift in the expression of homing chemokines and structural deterioration of the stromal network in T cell zones. Treatment with IL-7/mAb complexes can restore naive T cell homeostatic proliferation in aged mice. Our data suggests that homeostatic mechanisms that support the naive T cell pool deteriorate with age.11128Ysciescopu

IL-7 and IL-15 differentially regulate CD8+ T-cell subsets during contraction of the immune response

Although it is known that interleukin-7 (IL-7) and IL-15 influence the survival and turnover of CD8+ T cells, less is known about how these cytokines affect different subsets during the course of the immune response. We find that IL-7 and IL-15 differentially regulate CD8+ T-cell subsets defined by KLRG1 and CD127 expression during the contraction phase of the immune response. The provision of IL-15, or the related cytokine IL-2, during contraction led to the preferential accumulation of KLRG1hiCD127lo CD8+ T cells, whereas provision of IL-7 instead favored the accumulation of KLRG1loCD127hi cells. While IL-7 and IL-15 both induced proliferation of KLRG1lo cells, KLRG1hi cells exhibited an extraordinarily high level of resistance to cytokine-driven proliferation in vivo despite their dramatic accumulation upon IL-15 administration. These results suggest that IL-15 and IL-2 greatly improve the survival of KLRG1hi CD8+ T cells, which are usually destined to perish during contraction, without inducing proliferation. As the availability of IL-15 and IL-2 is enhanced during periods of extended inflammation, our results suggest a mechanism in which a population of cytokine-dependent KLRG1hi CD8+ T cells is temporarily retained for improved immunity. Consideration of these findings may aid in the development of immunotherapeutic strategies against infectious disease and cancer