Memory T-Cell Predominance Following T-Cell Depletional Therapy Derives from Homeostatic Expansion of Naive T Cells

Regulation of cell numbers and organ size in multicellular organisms is an important principle in biology. Experimental data in developmental biology indicate that there are mechanisms by which organs sense their total mass, linked to the regulation of cell size and proliferation, but not solely determined by either.1,2 Active monitoring of organ size is suggested by regeneration experiments following removal of part of an organ; this has been best illustrated by the regeneration of mammalian liver after partial hepatectomy.3 Another example is the demonstration that, following transplantation of multiple spleen fragments, the total spleen graft mass tends to reach a plateau which is in the range of variation of normal spleen weights.4 There are a multitude of mechanisms that regulate the number of cells (reviewed in ref. 1). For instance, the number of cell divisions may be predetermined, as in the nematode Caenorhabditis elegans,5 or divisions may stop after a given time interval (a mechanism for cell number control used in cardiac myocytes). Furthermore, hormones and components of signal-transduction pathways regulate growth and cell division, e.g. growth hormone6 and components of the insulin-signalling pathway.7 Another widely used principle in biological systems is competition for limiting resources, such as secretory molecules or cell-contact mechanisms. This is evident, for instance, in the control of oligodendrocyte precursors, which are regulated via the concentration of platelet-derived growth factor, whereas the number of mature oligodendrocytes is related to axon-dependent survival signals that are limited in amount and assure that the final number of oligodendrocytes is matched to the number of axons.8–10 In the mammalian immune system, size control checks maintain the number of peripheral T cells at more or less constant levels. This is not the result of a finite capacity for cell division, as it has been shown that T cells, following serial transfer into irradiated hosts, are able to divide up to 56 times in vivo, an expansion potential similar to that of colony-forming units.11 Thus, alternative mechanisms are involved in controlling the numbers of T cells in the face of ongoing new production from the thymus (at least for a certain period in development) and continuous expansion in response to antigenic stimuli. The American physiologist, Walter Cannon, introduced the term ‘homeostasis’ to describe the tendency of an organism to restore its original status in the face of unexpected disturbances.12 Permutations of this term are now widely used by immunologists referring to various response modes of T cells when the equilibrium is disturbed. The intrinsic dynamics of the immune system pose constant challenges threatening the equilibrium, and it is therefore understandable that the immune system has developed several layers of homeostatic control mechanisms.

Immune Reconstitution: How It Should Work, What's Broken, and Why It Matters

Human cytomegalovirus (HCMV), a member of the betaherpesvirus family, is an omnipresent pathogen worldwide. Primary HCMV infection elicits robust responses from both the innate and adaptive branches of the immune system. The T-cell response is extraordinary large; on average 10% of the total circulating memory compartment of both the CD4 and CD8 T-cell subsets is specific for HCMV, which makes this virus possibly the most immunogenic microbe for the human immune system. However, despite the extensive immune response, HCMV is not cleared and persists in the host due to its numerous immune evasion mechanisms. Both, primary infection and long-term persistence of HCMV are largely subclinical for the majority of individuals, but HCMV virus is linked to considerable morbidity in immunologically immature and immunocompromised individuals. The role of HCMV infection in immunocompetent hosts has gained considerable interest, and has led to insights that favor a neutral or even beneficial co-existence, but also HCMV-driven detrimental consequences have been reported especially in the elderly. This differential outcome of HCMV infection might be related to the huge variability in the size and phenotype of HCMV-specific T-cell responses among individuals, caused by the differences in infectious dose and the immunocompetence of the host. The interactions between CMV and the immune system were discussed at the 5th International Workshop on CMV and Immunosenescence. Here, we highlight some of the key findings discussed in the meeting, with an emphasis on the particular role of HCMV in memory T-cell formation.

Generation and Functional Capacity of Polyclonal Alloantigen-Specific Memory CD4 T Cells

HIV-1 establishes a lifelong infection in the human body, but host factors that influence viral persistence remain poorly understood. Cell-intrinsic characteristics of CD4 T cells, the main target cells for HIV-1, may affect the composition of the latent viral reservoir by altering the susceptibility to CD8 T-cell-mediated killing. We observed that susceptibilities of CD4 T cells to CD8 T-cell-mediated killing, as determined in direct ex vivo assays, were significantly higher in persons with natural control of HIV-1 (elite controllers) than in individuals effectively treated with antiretroviral therapy. These differences were most pronounced in naive and in terminally differentiated CD4 T cells and corresponded to a reduced viral reservoir size in elite controllers. Interestingly, the highest susceptibility to CD8 T-cell-mediated killing and lowest reservoirs of cell-associated HIV-1 DNA was consistently observed in elite controllers expressing the protective HLA class I allele B57. These data suggest that the functional responsiveness of host CD4 T cells to cytotoxic effects of HIV-1-specific CD8 T cells can contribute to shaping the structure and composition of the latently infected CD4 T-cell pool.

Combined mTOR Inhibition and OX40 Agonism Enhances CD8+ T Cell Memory and Protective Immunity Produced by Recombinant Adenovirus Vaccines

Liver-Primed Memory T Cells Generated under Noninflammatory Conditions Provide Anti-infectious Immunity

Recipient Hematopoietic, but Not Non-Hematopoietic, Antigen-Presenting Cells Are Indispensable for CD4+ T-Cell-Mediated Xenogeneic Graft-Versus-Host Disease

Allo-reactive memory T cells are a major barrier for induction of immunological tolerance to allografts in humans. Here, we report that stimulation of unfractionated human T cells with TLR-stimulated allogeneic plasmacytoid dendritic cells (pDCs) induces CD8(+) regulatory T cells (Tregs) that inhibit T-cell allo-responses, including those of memory T cells. CD3(+) T cells were primed for 7 days with allogeneic pDCs that had been pre-stimulated with TLR-7 or TLR-9 ligands. While the T cells proliferated and produced cytokines during the priming culture, they were profoundly hypo-responsive to re-stimulation with the same allo-antigen in a second culture. Moreover, T cells primed by pDCs exerted donor-specific suppression on allo-responses of both unfractionated and memory CD3(+) T cells. The regulatory capacity of pDC-primed T cells was confined to CD8(+) LAG-3(+) Foxp3(+) CTLA-4(+) T cells, which suppressed allogeneic T-cell responses through a CTLA-4-dependent mechanism. Induction of CD8(+) Tregs by pDCs could be partially prevented by 1-methyl tryptophan, an inhibitor of indoleamine 2,3-dioxygenase. In conclusion, stimulation of human T cells by TLR-stimulated allogeneic pDCs induces CD8(+) Tregs that inhibit allogeneic T-cell responses, including memory T cells. Donor-derived pDCs may be considered as an immunotherapeutic tool to prevent activation of the recipient allo-reactive (memory) T-cell repertoire after allogeneic transplantation.

The Gastrointestinal Tract and AIDS Pathogenesis

Ultraviolet B Suppresses Immunity by Inhibiting Effector and Memory T Cells

Macrophage- and Dendritic-Cell-Derived Interleukin-15 Receptor Alpha Supports Homeostasis of Distinct CD8+ T Cell Subsets

Pharmacologic control of homeostatic and antigen-driven proliferation to target HIV-1 persistence

T cells present in lymphopenic environments undergo spontaneous (homeostatic) proliferation resulting in expansion of the memory T cell pool. Homeostatically generated memory T cells protect the host against infection but can cause autoimmunity and allograft rejection. Therefore, understanding the mechanisms that regulate homeostatic T cell proliferation is germane to clinical settings in which lymphodepletion is used. In this study, we asked whether NK cells, which regulate immune responses in lymphocyte-replete hosts, also regulate homeostatic T cell proliferation under lymphopenic conditions. We found that T cells transferred into genetically lymphocyte-deficient RAG-/- mice proliferate faster and generate more CD8+ memory T cells if NK cells were absent. CD8+ T cells that underwent homeostatic proliferation in the presence of NK cells generated mostly effector memory (CD44highCD62Llow) lymphocytes, whereas those that divided in the absence of NK cells were skewed toward central memory (CD44highCD62Lhigh). The latter originated predominantly from proliferation of the "natural" central memory CD8+ T cell pool. Regulation of homeostatic proliferation by NK cells occurred independent of perforin but was reversed by excess IL-15. Importantly, NK depletion enhanced CD8+ T cell recovery in T cell-depleted wild-type mice and accelerated rejection of skin allografts, indicating that regulation of homeostatic proliferation by NK cells is not restricted to genetically lymphocyte-deficient animals. These results demonstrate that NK cells downregulate homeostatic CD8+ T cell proliferation in lymphopenic environments by competing for IL-15. Concomitant NK and T cell depletion may be undesirable in transplant recipients because of enhanced expansion of memory CD8+ T cells that increase the risk of rejection.

Cytokine-Mediated Programmed Proliferation of Virus-Specific CD8+ Memory T Cells