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      CD8(+) T cells: foot soldiers of the immune system.

      Immunity
      Animals, Antigen Presentation, CD8-Positive T-Lymphocytes, immunology, Cell Differentiation, Cell Movement, Cell Proliferation, Cytokines, Cytotoxicity, Immunologic, Histocompatibility Antigens Class I, Homeostasis, Humans, Immune System, cytology, growth & development, Immunologic Memory, Lymphocyte Activation, Th1-Th2 Balance

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          Abstract

          Resting naive CD8(+) T cells have an astounding capacity to react to pathogens by massive expansion and differentiation into cytotoxic effector cells that migrate to all corners of the body to clear the infection. The initial interaction with antigen-presenting cells in the central lymphoid organs drives an orchestrated program of differentiation aimed at producing sufficient numbers of effectors to get the job done without resulting in clonal exhaustion. Interactions with antigen-presenting cells and other immune cells continue at the site of infection to regulate further on-site expansion and differentiation, all with the goal of protecting the host with minimal bystander tissue damage. Here we review recent advances in CD8(+) T cell recognition of antigen in lymphoid as well as in nonlymphoid tissues in the periphery, and how CD8(+) T cell expansion and differentiation are controlled in these contexts. Copyright © 2011 Elsevier Inc. All rights reserved.

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          Most cited references57

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          T-cell priming by dendritic cells in lymph nodes occurs in three distinct phases.

          Primary T-cell responses in lymph nodes (LNs) require contact-dependent information exchange between T cells and dendritic cells (DCs). Because lymphocytes continually enter and leave normal LNs, the resident lymphocyte pool is composed of non-synchronized cells with different dwell times that display heterogeneous behaviour in mouse LNs in vitro. Here we employ two-photon microscopy in vivo to study antigen-presenting DCs and naive T cells whose dwell time in LNs was synchronized. During the first 8 h after entering from the blood, T cells underwent multiple short encounters with DCs, progressively decreased their motility, and upregulated activation markers. During the subsequent 12 h T cells formed long-lasting stable conjugates with DCs and began to secrete interleukin-2 and interferon-gamma. On the second day, coinciding with the onset of proliferation, T cells resumed their rapid migration and short DC contacts. Thus, T-cell priming by DCs occurs in three successive stages: transient serial encounters during the first activation phase are followed by a second phase of stable contacts culminating in cytokine production, which makes a transition into a third phase of high motility and rapid proliferation.
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            Glutamine uptake and metabolism are coordinately regulated by ERK/MAPK during T lymphocyte activation.

            Activation of a naive T cell is a highly energetic event, which requires a substantial increase in nutrient metabolism. Upon stimulation, T cells increase in size, rapidly proliferate, and differentiate, all of which lead to a high demand for energetic and biosynthetic precursors. Although amino acids are the basic building blocks of protein biosynthesis and contribute to many other metabolic processes, the role of amino acid metabolism in T cell activation has not been well characterized. We have found that glutamine in particular is required for T cell function. Depletion of glutamine blocks proliferation and cytokine production, and this cannot be rescued by supplying biosynthetic precursors of glutamine. Correlating with the absolute requirement for glutamine, T cell activation induces a large increase in glutamine import, but not glutamate import, and this increase is CD28-dependent. Activation coordinately enhances expression of glutamine transporters and activities of enzymes required to allow the use of glutamine as a Krebs cycle substrate in T cells. The induction of glutamine uptake and metabolism requires ERK function, providing a link to TCR signaling. Together, these data indicate that regulation of glutamine use is an important component of T cell activation. Thus, a better understanding of glutamine sensing and use in T cells may reveal novel targets for immunomodulation.
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              Stromal cell networks regulate lymphocyte entry, migration, and territoriality in lymph nodes.

              After entry into lymph nodes (LNs), B cells migrate to follicles, whereas T cells remain in the paracortex, with each lymphocyte type showing apparently random migration within these distinct areas. Other than chemokines, the factors contributing to this spatial segregation and to the observed patterns of lymphocyte movement are poorly characterized. By combining confocal, electron, and intravital microscopy, we showed that the fibroblastic reticular cell network regulated naive T cell access to the paracortex and also supported and defined the limits of T cell movement within this domain, whereas a distinct follicular dendritic cell network similarly served as the substratum for movement of follicular B cells. These results highlight the central role of stromal microanatomy in orchestrating cell migration within the LN.
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