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IL-7 regulates basal homeostatic proliferation of antiviral CD4+T cell memory.

ABSTRACT: Heightened protection from infectious disease as conferred by vaccination or pathogen exposure relies on the effective generation and preservation of specific immunological memory. T cells are irreducibly required for the control of most viral infections, and maintenance of CD8(+)T cell memory is regulated by at least two cytokines, IL-7 and IL-15, which support survival (IL-7, IL-15) and basal homeostatic proliferation (IL-15) of specific CD8(+) memory T cells (T(M)). In contrast, the factors governing the homeostasis of pathogen-specific CD4(+)T(M) remain at present unknown. Here, we used a physiologic in vivo model system for viral infection to delineate homeostatic features and mechanisms of antiviral CD4(+)T(M) preservation in direct juxtaposition to CD8(+)T cell memory. Basal homeostatic proliferation is comparable between specific CD4(+) and CD8(+)T(M) and independent of immunodominant determinants and functional avidities but regulated in a tissue-specific fashion. IL-7, identified as the dominant cytokine, and IL-15, an accessory cytokine, regulate basal homeostatic proliferation and survival of antiviral CD4(+)T(M). Interestingly, a role for these cytokines in regulation of CD4(+)T cell memory is not readily discernible in the generic "memory-phenotype" population, apparently a consequence of its heterogeneous composition. We also describe a prominent, nonredundant role for IL-7 in supporting basal homeostatic proliferation of CD8(+)T(M). We propose that homeostatic control of antiviral CD4(+) and CD8(+) T cell memory is fundamentally similar and characterized by quantitative, rather than qualitative, differences.

SUBMITTER: Lenz DC

PROVIDER: S-EPMC438981 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Memory CD4 T cells induce selective expression of IL-27 in CD8+ dendritic cells and regulate homeostatic naive T cell proliferation.

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| S-EPMC3244513 | biostudies-literature

Antiviral CD4+ memory T cells are IL-15 dependent.

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| S-EPMC3855745 | biostudies-literature

IL-7-dependent STAT1 activation limits homeostatic CD4+ T cell expansion.

Project description:IL-7 regulates homeostatic mechanisms that maintain the overall size of the T cell pool throughout life. We show that, under steady-state conditions, IL-7 signaling is principally mediated by activation of signal transducers and activators of transcription 5 (STAT5). In contrast, under lymphopenic conditions, there is a modulation of STAT1 expression resulting in an IL-7-dependent STAT1 and STAT5 activation. Consequently, the IL-7-induced transcriptome is altered with enrichment of IFN-stimulated genes (ISGs). Moreover, STAT1 overexpression was associated with reduced survival in CD4+ T cells undergoing lymphopenia-induced proliferation (LIP). We propose a model in which T cells undergoing LIP upregulate STAT1 protein, "switching on" an alternate IL-7-dependent program. This mechanism could be a physiological process to regulate the expansion and size of the CD4+ T cell pool. During HIV infection, the virus could exploit this pathway, leading to the homeostatic dysregulation of the T cell pools observed in these patients.

| S-EPMC5752389 | biostudies-literature

Homeostatic proliferation fails to efficiently reactivate HIV-1 latently infected central memory CD4+ T cells.

Project description:Homeostatic proliferation ensures the longevity of central memory T-cells by inducing cell proliferation in the absence of cellular differentiation or activation. This process is governed mainly by IL-7. Central memory T-cells can also be stimulated via engagement of the T-cell receptor, leading to cell proliferation but also activation and differentiation. Using an in vitro model of HIV-1 latency, we have examined in detail the effects of homeostatic proliferation on latently infected central memory T cells. We have also used antigenic stimulation via anti-CD3/anti-CD28 antibodies and established a comparison with a homeostatic proliferation stimulus, to evaluate potential differences in how either treatment affects the dynamics of latent virus populations. First, we show that homeostatic proliferation, as induced by a combination of IL-2 plus IL-7, leads to partial reactivation of latent HIV-1 but is unable to reduce the size of the reservoir in vitro. Second, latently infected cells are able to homeostatically proliferate in the absence of viral reactivation or cell differentiation. These results indicate that IL-2 plus IL-7 may induce a detrimental effect by favoring the maintenance of the latent HIV-1 reservoir. On the other hand, antigenic stimulation efficiently reactivated latent HIV-1 in cultured central memory cells and led to depletion of the latently infected cells via virus-induced cell death.

| S-EPMC3188522 | biostudies-literature

C/EBP? regulates homeostatic and oncogenic gastric cell proliferation.

Project description:Cancer of the stomach is among the leading causes of death from cancer worldwide. The transcription factor C/EBP? is frequently overexpressed in gastric cancer and associated with the suppression of the differentiation marker TFF1. We show that the murine C/EBP? knockout stomach displays unbalanced homeostasis and reduced cell proliferation and that tumorigenesis of human gastric cancer xenograft is inhibited by knockdown of C/EBP?. Cross-species comparison of gene expression profiles between C/EBP?-deficient murine stomach and human gastric cancer revealed a subset of tumors with a C/EBP? signature. Within this signature, the RUNX1t1 tumor suppressor transcript was down-regulated in 38 % of gastric tumor samples. The RUNX1t1 promoter was frequently hypermethylated and ectopic expression of RUNX1t1 in gastric cancer cells inhibited proliferation and enhanced TFF1 expression. These data suggest that the tumor suppressor activity of both RUNX1t1 and TFF1 are mechanistically connected to C/EBP? and that cross-regulation between C/EBP?-RUNX1t1-TFF1 plays an important role in gastric carcinogenesis.Key messageC/EBP? controls proliferation and differentiation balance in the stomach. Homeostatic differentiation/proliferation balance is altered in gastric cancer. RUNX1t1 is a C/EBP?-associated tumor suppressor. RUNX1t1 negatively regulates C/EBP? pro-oncogenic functions.

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Natural Killer Cell Plasticity During IL-15-driven Homeostatic Proliferation

Project description:Here we performed single-cell RNA sequencing to address repertoire stability and subset plasticity during IL-15 driven homeostatic proliferation. Sorted NK cell subsets representing discrete stages of NK cell differentiation are compared with the corresponding subsets after proliferation and further sorted into two subsets depending on the rate of proliferation.

| EGAS00001003946 | EGA

Natural Killer Cell Plasticity During IL-15-driven Homeostatic Proliferation

Project description:Data Access Committee EGAC00001001346

| EGAC00001001346 | EGA

Autoimmune arthritis associated with mutated interleukin (IL)-6 receptor gp130 is driven by STAT3/IL-7-dependent homeostatic proliferation of CD4+ T cells.

Project description:Mice homozygous for the F759 mutation in the gp130 interleukin (IL)-6 receptor subunit have enhanced gp130-mediated signal transducer and activator of transcription (STAT)3 activation and spontaneously developed a lymphocyte-mediated rheumatoid arthritis-like joint disease. Here, we show that the development of the disease is dependent on both major histocompatibility complex (MHC) II-restricted CD4+ T cells and IL-6 family cytokines. In spite of the necessity for CD4+ T cells, the gp130 mutation was only required in nonhemtopoietic cells for the disease. The gp130 mutation resulted in enhanced production of IL-7. Conditional knockout of STAT3 in nonlymphoid cells showed that the enhancement of IL-7 production was dependent on STAT3 activation by IL-6 family cytokines. Homeostatic proliferation of CD4+ T cells was enhanced in gp130 mutant mice and acceleration of homeostatic proliferation enhanced the disease, whereas the inhibition of homeostatic proliferation suppressed the disease. Anti-IL-7 antibody treatment inhibited not only the enhanced homeostatic proliferation, but also the disease in gp130 mutant mice. Thus, our results show that autoimmune disease in gp130 mutant mice is caused by increased homeostatic proliferation of CD4+ T cells, which is due to elevated production of IL-7 by nonhematopoietic cells as a result of IL-6 family cytokine-gp130-STAT3 signaling.

| S-EPMC2118324 | biostudies-other

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