The memory T cell pool functions as a dynamic repository of antigen-experienced T lymphocytes that accumulate over the lifetime of the individual. Recent studies indicate that memory T lymphocytes contain distinct populations of central memory (TCM) and effector memory (TEM) cells characterized by distinct homing capacity and effector function. This review addresses the heterogeneity of TCM and TEM, their differentiation stages, and the current models for their generation and maintenance in humans and mice.

Central Memory and Effector Memory T Cell Subsets: Function, Generation, and Maintenance

The naive and memory T lymphocyte pools are maintained through poorly understood homeostatic mechanisms that may include signaling via cytokine receptors. We show that interleukin-7 (IL-7) plays multiple roles in regulating homeostasis of CD8+ T cells. We found that IL-7 was required for homeostatic expansion of naive CD8+ and CD4+ T cells in lymphopenic hosts and for CD8+ T cell survival in normal hosts. In contrast, IL-7 was not necessary for growth of CD8+ T cells in response to a virus infection but was critical for generating T cell memory. Up-regulation of Bcl-2 in the absence of IL-7 signaling was impaired after activation in vivo. Homeostatic proliferation of memory cells was also partially dependent on IL-7. These results point to IL-7 as a pivotal cytokine in T cell homeostasis.

https://www.cytoluminator.com/cancer-photodynamic-therapy/IL-7%20memory%20CD8%20T%20cells.pdf

Interleukin-7 mediates the homeostasis of naïve and memory CD8 T cells in vivo.

C57BL/6 mice genetically deficient in interleukin 15 (IL-15−/− mice) were generated by gene targeting. IL-15−/− mice displayed marked reductions in numbers of thymic and peripheral natural killer (NK) T cells, memory phenotype CD8+ T cells, and distinct subpopulations of intestinal intraepithelial lymphocytes (IELs). The reduction but not absence of these populations in IL-15−/− mice likely reflects an important role for IL-15 for expansion and/or survival of these cells. IL-15−/− mice lacked NK cells, as assessed by both immunophenotyping and functional criteria, indicating an obligate role for IL-15 in the development and functional maturation of NK cells. Specific defects associated with IL-15 deficiency were reversed by in vivo administration of exogenous IL-15. Despite their immunological defects, IL-15−/− mice remained healthy when maintained under specific pathogen-free conditions. However, IL-15−/− mice are likely to have compromised host defense responses to various pathogens, as they were unable to mount a protective response to challenge with vaccinia virus. These data reveal critical roles for IL-15 in the development of specific lymphoid lineages. Moreover, the ability to rescue lymphoid defects in IL-15−/− mice by IL-15 administration represents a powerful means by which to further elucidate the biological roles of this cytokine.

/pdf/reversible-defects-in-natural-killer-and-memory-cd8-t-cell-2meygczf1f.pdf

Reversible Defects in Natural Killer and Memory Cd8 T Cell Lineages in Interleukin 15–Deficient Mice

Two seemingly unrelated hallmarks of memory CD8(+) T cells are cytokine-driven proliferative renewal after pathogen clearance and a latent effector program in anticipation of rechallenge. Memory CD8(+) T cells and natural killer cells share cytotoxic potential and dependence on the growth factor interleukin 15. We now show that mice with compound mutations of the genes encoding the transcription factors T-bet and eomesodermin were nearly devoid of several lineages dependent on interleukin 15, including memory CD8(+) T cells and mature natural killer cells, and that their cells had defective cytotoxic effector programming. Moreover, T-bet and eomesodermin were responsible for inducing enhanced expression of CD122, the receptor specifying interleukin 15 responsiveness. Therefore, these key transcription factors link the long-term renewal of memory CD8(+) T cells to their characteristic effector potency.

Effector and memory CD8 + T cell fate coupled by T-bet and eomesodermin

https://www.cell.com/immunity/pdf/S1074-7613(08)00506-2.pdf

Homeostasis of naive and memory T cells.

https://www.cell.com/immunity/pdf/S1074-7613(00)80664-0.pdf

IL-15 receptor maintains lymphoid homeostasis by supporting lymphocyte homing and proliferation

Background—A peptide derived from Antrum Mucosal Protein (AMP)-18 (gastrokine-1) reduces the extent of mucosal erosions and clinical severity in mice with dextran sulfate sodium (DSS)-induced colonic injury. The present study set out to determine if AMP peptide was also therapeutic for immuneand cytokine-mediated mouse models of intestinal injury and inflammatory bowel diseases (IBD) by enhancing and stabilizing tight junctions (TJs). Methods—Therapeutic effects of AMP peptide were examined in interleukin-10 deficient and a T cell adoptive transfer models of colitis in immunodeficient recombinase activating gene-1 knock-out (RAG-1−/−) mice. Mechanisms by which AMP peptide enhances barrier function and structure were studied ex vivo using intestine and colon from mice given lipopolysaccharide (LPS), and in AMP-18 deficient mice given DSS. Results—In interleukin-10 deficient mice given piroxicam, AMP peptide enhanced recovery after weight loss, protected against colon shortening and segmental dilation, and reduced the colitis activity score. In the T cell transfer model, treatment with the peptide protected against colon shortening. In mice given LPS in vivo to induce gut injury, AMP peptide prevented the onset of, and reversed established intestinal hyperpermeability by targeting TJ proteins and perijunctional actin. AMP-18-deficient mice challenged with DSS exhibited increased mortality, developed erosions in the colon, and had lower levels of ZO-1 in TJs than heterozygous littermates or wild-type mice. Conclusions—The results indicate that AMP-18/peptide may serve a protective role against injury along the GI mucosal barrier, and recommend further development of AMP peptide as a novel agent to treat patients with IBD. Correspondence authors: David L. Boone, Indiana University School of Medicine, 1234 N. Notre Dame Ave, RC122, South Bend, IN 46617, Telephone: 574-631-6040., David.Boone.16@nd.edu. F. Gary Toback, The University of Chicago, Department of Medicine, MC5100, 5841 South Maryland, Avenue, Chicago, IL 60637, Telephone: 773-702-1476, Fax: 773-702-5818., gtoback@medicine.bsd.uchicago.edu. §Equal contribution. #Current address: Indiana University School of Medicine, South Bend, IN 46617 HHS Public Access Author manuscript Inflamm Bowel Dis. Author manuscript; available in PMC 2016 October 01. Published in final edited form as: Inflamm Bowel Dis. 2015 October ; 21(10): 2393–2402. doi:10.1097/MIB.0000000000000499. A uhor M anscript

James P Lodolce

Papers

IL-15 receptor maintains lymphoid homeostasis by supporting lymphocyte homing and proliferation

AMP peptide targets tight junctions to protect and heal barrier structure and function in models of IBD.