THE MAMMALIAN IMMUNE SYSTEM can be broadly divided into two main arms: innate and adaptive immunity. As its name implies, the cells and receptors of the innate immune system are critical for the rapid recognition of the infectious agent and initiating a proinflammatory response. While the inflammation generated by innate immune cells [neutrophils, macrophages, monocytes, natural killer (NK) cells, dendritic cells (DCs), etc.] is important in the initial containment of the infection, it also informs and directs the expansion and differentiation of adaptive immune cells. Responding to the inflammatory environment created by the innate response, cells of the adaptive arm of the immune response (B cells, ␣␤ T cells, and ␥␦ T cells) are stimulated to expand in number (proliferate) and to differentiate into cells with a range of functions appropriate for the immunological challenge. Upon elimination of the invading pathogen, the majority of adaptive cells die and leave behind an (evergrowing) array of memory cell subsets. These memory cells offer a diversity of migratory properties and functions, collectively mediating a rapid and protective immune response upon reinfection. Thus, the major advantages of an adaptive response to the host are twofold. First, it allows the host to form an immune response that is specifically tailored to the invading pathogen. Second, it forms a pool of memory cells from these specific effectors that can last for many years, capable of protecting the host against reinfection by their rapid response. This combination of specificity and memory are the mechanistic underpinnings for the clinical success of vaccination.Critical to almost all functions of the adaptive immune response is the activation and programming of T cells from their naïve/resting state. Although there is much more to be learned, we now have a good basic understanding of the signals and cell types involved in the various stages of the T cell response initiated within the secondary lymphoid organs (SLOs). To provide a comprehensive overview, this review will summarize the T cell response broken down into three major stages: activation, differentiation, and memory formation. We will then assemble these components into a description of the anatomy of an immune response and its relationship to productive immune protection. T Cell ActivationThe primary mediator of T cell activation is the T cell receptor (TCR). Generated by recombination of genomic DNA sequences during T cell development in the thymus, each TCR is essentially unique and is responsible for the specificity of each T cell (26,79). Successful recombination of a functional TCR and emergence from the thymus results in a resting, "naïve" T cell capable mainly of migrating through the secondary lymphoid tissues (lymph nodes and spleen) and peripheral circulation but as yet incapable of producing any kind of response that could protect against infectious challenge. Producing a T cell that is capable of mediating immune protection first requires "activation" of the naïve ...

Virtual memory cells (VM) are an antigen-specific, memory phenotype CD8 T-cell subset found in lymphoreplete, unchallenged mice. Previous studies indicated that VM cells were the result of homeostatic proliferation (HP) resembling the proliferation observed in a lymphopenic environment. Here we demonstrate that HP is ongoing in lymphoreplete mice, the degree of which is dictated by the number of naive CD8 T cells with a sufficiently high affinity for self-antigen interacting with peripheral IL-15. VM cell transcriptional profiles suggest a capacity to mediate protective immunity via antigen non-specific bystander killing, a function we show is dependent on IL-15. Finally, we show a VM-like population of human cells that accumulate with age and traffic to the liver, displaying phenotypic and functional attributes consistent with the bystander protective functions of VM cells identified in the mouse. These data identify developmental and functional attributes of VM cells, including their likely role in protective immunity.

Various populations of memory phenotype CD8+ T cells have been described over the last 15–20 years, all of which possess elevated effector functions relative to naïve phenotype cells. Using a technique for isolating antigen specific cells from unprimed hosts, we recently identified a new subset of cells, specific for nominal antigen, but phenotypically and functionally similar to memory cells arising as a result of homeostatic proliferation (HP). We show here that these “Virtual Memory” cells are independent of previously identified “innate memory” cells, arising as a result of their response to IL-15 trans-presentation by lymphoid tissue-resident CD8α+ DCs in the periphery. The absence of IL-15, CD8+ T cell expression of either CD122 or Eomes, or of CD8a+ DCs all lead to the loss of Virtual Memory cells in the host. Our results show that CD8+ T cell homeostatic expansion is an active process within the non-lymphopenic environment, is mediated by IL-15, and produces antigen inexperienced memory cells which retain the capacity to respond to nominal antigen with memory-like function. Preferential engagement of these “Virtual Memory” T cells into a vaccine response could dramatically enhance the rate by which immune protection develops.

Memory-phenotype CD8+ T cells exist in substantial numbers within hosts that have not been exposed to either foreign antigen or overt lymphopenia. These antigen-inexperienced memory-phenotype T cells can be divided into two major subsets: ‘innate memory’ T cells and ‘virtual memory’ T cells. Although these two subsets are nearly indistinguishable by surface markers alone, notable developmental and functional differences exist between the two subsets, which suggests that they represent distinct populations. In this Opinion article, we review the available literature on each subset, highlighting the key differences between these populations. Furthermore, we suggest a unifying model for the categorization of antigen-inexperienced memory-phenotype CD8+ T cells.

SUMMARY The relationship between B cells and CD4 T cells has been carefully studied, revealing a collaborative effort in which B cells promote the activation, differentiation, and expansion of CD4 T cells while the so-called “helper” cells provide signals to B cells, influencing their class switching and fate. Interactions between B cells and CD8 T cells are not as well studied, although CD8 T cells exhibit an accelerated contraction after certain infections in B-cell-deficient mice. Here, we find that B cells significantly enhance primary CD8 T cell responses after vaccination. Moreover, memory CD8 numbers and function are impaired in B-cell-deficient animals, leading to increased susceptibility to bacterial challenge. We also show that interleukin-27 production by B cells contributes to their impact on primary, but not memory, CD8 responses. Better understanding of the interactions between CD8 T cells and B cells may aid in the design of more effective future vaccine strategies.

It is common practice for researchers to use antibodies to remove a specific cell type to infer its function. However, it is difficult to completely eliminate a cell type and there is often limited or no information as to how the cells which survive depletion are affected. This is particularly important for CD8+ T cells for two reasons. First, they are more resistant to mAb-mediated depletion than other lymphocytes. Second, targeting either the CD8α or CD8β chain could induce differential effects. We show here that two commonly used mAbs, against either the CD8α or CD8β subunit, can differentially affect cellular metabolism. Further, in vivo treatment leaves behind a population of CD8+ T cells with different phenotypic and functional attributes relative to each other or control CD8+ T cells. The impact of anti-CD8 antibodies on CD8+ T cell phenotype and function indicates the need to carefully consider the use of these, and possibly other “depleting” antibodies, as they could significantly complicate the interpretation of results or change the outcome of an experiment. These observations could impact how immunotherapy and modulation of CD8+ T cell activation is pursued.

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