Blowing on Embers: Commensal Microbiota and Our Immune System

Vertebrates have co-evolved with microorganisms resulting in a symbiotic relationship, which plays an important role in health and disease. Skin and mucosal surfaces are colonized with a diverse population of commensal microbiota, over 1000 species, outnumbering the host cells by 10-fold. In the past 40 years, studies have built on the idea that commensal microbiota is in constant contact with the host immune system and thus influence immune function. Recent studies, focusing on mutualism in the gut, have shown that commensal microbiota seems to play a critical role in the development and homeostasis of the host immune system. In particular, the gut microbiota appears to direct the organization and maturation of lymphoid tissues and acts both locally and systemically to regulate the recruitment, differentiation, and function of innate and adaptive immune cells. While the pace of research in the area of the mucosal–immune interface has certainly intensified over the last 10 years, we are still in the early days of this field. Illuminating the mechanisms of how gut microbes shape host immunity will enhance our understanding of the causes of immune-mediated pathologies and improve the design of next-generation vaccines. This review discusses the recent advances in this field, focusing on the close relationship between the adaptive immune system and commensal microbiota, a constant and abundant source of foreign antigens

Functional and Homeostatic impact of Age-Related Changes in Lymph node Stroma

Adults over 65 years of age are more vulnerable to infectious disease and show poor responses to vaccination relative to those under 50. A complex set of age-related changes in the immune system is believed to be largely responsible for these defects. These changes, collectively termed immune senescence, encompass alterations in both the innate and adaptive immune systems, in the microenvironments where immune cells develop or reside, and in soluble factors that guide immune homeostasis and function. While age-related changes in primary lymphoid organs (bone marrow, and, in particular, the thymus, which involutes in the first third of life) have been long appreciated, changes affecting aging secondary lymphoid organs, and, in particular, aging lymph nodes (LNs) have been less well characterized. Over the last 20 years, LN stromal cells have emerged as key players in maintaining LN morphology and immune homeostasis, as well as in coordinating immune responses to pathogens. Here, we review recent progress in understanding the contributions of LN stromal cells to immune senescence. We discuss approaches to understand the mechanisms behind the decline in LN stromal cells and conclude by considering potential strategies to rejuvenate aging LN stroma to improve immune homeostasis, immune responses, and vaccine efficacy in the elderly.113Ysciescopu

A major histocompatibility complex class I–dependent subset of memory phenotype CD8+ cells

Most memory phenotype (MP) CD44hi CD8+ cells are resting interleukin (IL)-15–dependent cells characterized by high expression of the IL-2/IL-15 receptor β (CD122). However, some MP CD8+ cells have a CD122lo phenotype and are IL-15 independent. Here, evidence is presented that the CD122lo subset of MP CD8+ cells is controlled largely by major histocompatibility complex (MHC) class I molecules. Many of these cells display surface markers typical of recently activated T cells (CD62Llo, CD69hi, CD43hi, and CD127lo) and show a high rate of background proliferation. Cells with this phenotype are highly enriched in common γ chain–deficient mice and absent from MHC-I−/− mice. Unlike CD122hi CD8+ cells, CD122lo MP CD8+ cells survive poorly after transfer to MHC-I−/− hosts and cease to proliferate. Although distinctly different from typical antigen-specific memory cells, CD122lo MP CD8+ cells closely resemble the antigen-dependent memory CD8+ cells found in chronic viral infections

Aging Leads to Disturbed Homeostasis of Memory Phenotype CD8+ Cells

Examining the rate of in vivo T cell turnover (proliferation) in aged mice revealed a marked reduction in turnover at the level of memory-phenotype CD44hi CD8+ cells relative to young mice. Based on adoptive transfer experiments, the reduced turnover of aged CD44hi CD8+ cells reflected an inhibitory influence of the aged host environment. Aged CD44hi CD8+ cells also showed poor in vivo responses to IL-15 and IL-15–inducing agents, but responded well to IL-15 in vitro. Two mechanisms could account for the reduced turnover of aged CD44hi CD8+ cells in vivo. First, aging was associated with a prominent and selective increase in Bcl-2 expression in CD44hi CD8+ cells. Hence, the reduced turnover of aged CD44hi CD8+ cells may in part reflect the antiproliferative effect of enhanced Bcl-2 expression. Second, the impaired in vivo response of aged CD44hi CD8+ cells to IL-15 correlated with increased serum levels of type I interferons (IFN-I) and was largely reversed by injection of anti–IFN-I antibody. Hence the selective reduction in the turnover of aged CD44hi CD8+ cells in vivo may reflect the combined inhibitory effects of enhanced Bcl-2 expression and high IFN-I levels

Interleukin 7 Regulates the Survival and Generation of Memory CD4 Cells

Cytokines, particularly those of the common γ chain receptor family, provide extrinsic signals that regulate naive CD4 cell survival. Whether these cytokines are required for the maintenance of memory CD4 cells has not been rigorously assessed. In this paper, we examined the contribution of interleukin (IL) 7, a constitutively produced common γ chain receptor cytokine, to the survival of resting T cell receptor transgenic memory CD4 cells that were generated in vivo. IL-7 mediated the survival and up-regulation of Bcl-2 by resting memory CD4 cells in vitro in the absence of proliferation. Memory CD4 cells persisted for extended periods upon adoptive transfer into intact or lymphopenic recipients, but not in IL-7− mice or in recipients that were rendered deficient in IL-7 by antibody blocking. Both central (CD62L+) and effector (CD62L−) memory phenotype CD4 cells required IL-7 for survival and, in vivo, memory cells were comparable to naive CD4 cells in this regard. Although the generation of primary effector cells from naive CD4 cells and their dissemination to nonlymphoid tissues were not affected by IL-7 deficiency, memory cells failed to subsequently develop in either the lymphoid or nonlymphoid compartments. The results demonstrate that IL-7 can have previously unrecognized roles in the maintenance of memory in the CD4 cell population and in the survival of CD4 cells with a capacity to become memory cells

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

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

Overexpression of Interleukin (IL)-7 Leads to IL-15–independent Generation of Memory Phenotype CD8+ T Cells

Transgenic (TG) mice expressing a high copy number of interleukin (IL)-7 cDNA under the control of the major histocomaptability complex (MHC) class II promoter display a 10–20-fold increase in total T cell numbers. Here, we show that the increase in T cell numbers in IL-7 TG mice is most apparent at the level of memory phenotype CD44hi CD122hi CD8+ cells. Based on studies with T cell receptor (TCR) TG mice crossed to IL-7 TG mice, increased levels of IL-7 may provide costimulation for TCR recognition of self-MHC ligands and thus cause naive CD8+ cells to proliferate and differentiate into memory phenotype cells. In addition, a marked increase in CD44hi CD122hi CD8+ cells was found in IL-7 TG IL-15− mice. Since these cell are rare in normal IL-15− mice, the dependency of memory phenotype CD8+ cells on IL-15 can be overcome by overexpression of IL-7