Inflammatory cytokines drive CD4+ t-cell cycling and impaired responsiveness to interleukin 7 : implications for immune failure in HIV disease

Background. Systemic inflammation has been linked to a failure to normalize CD4+ T-cell numbers in treated human immunodeficiency virus (HIV) infection. Although inflammatory cytokines such as interleukin 6 (IL-6) are predictors of disease progression in treated HIV infection, it is not clear how or whether inflammatory mediators contribute to immune restoration failure. Methods. We examined the in vitro effects of IL-6 and interleukin 1\u3b2 (IL-1\u3b2) on peripheral blood T-cell cycling and CD127 surface expression. Results. The proinflammatory cytokine IL-1\u3b2 induces cell cycling and turnover of memory CD4+ T cells, and IL-6 can induce low-level cycling of naive T cells. Both IL-1\u3b2 and IL-6 can decrease T-cell surface expression and RNA levels of CD127, the interleukin 7 receptor \u3b1 chain (IL-7R\u3b1). Preexposure of healthy peripheral blood mononuclear cells (PBMCs) to IL-6 or IL-1\u3b2 attenuates IL-7-induced Stat5 phosphorylation and induction of the prosurvival factor Bcl-2 and the gut homing integrin \u3b14\u3b27. We found elevated expression of IL-1\u3b2 in the lymphoid tissues of patients with HIV infection that did not normalize with antiretroviral therapy. Conclusions. Induction of CD4+ T-cell turnover and diminished T-cell responsiveness to IL-7 by IL-1\u3b2 and IL-6 exposure may contribute to the lack of CD4+ T-cell reconstitution in treated HIV-infected subjects

Efforts of the human immune system to maintain the peripheral CD8+ T cell compartment after childhood thymectomy

Background Homeostatic mechanisms to maintain the T cell compartment diversity indicate an ongoing process of thymic activity and peripheral T cell renewal during human life. These processes are expected to be accelerated after childhood thymectomy and by the influence of cytomegalovirus (CMV) inducing a prematurely aged immune system. The study aimed to investigate proportional changes and replicative history of CD8+ T cells, of recent thymic emigrants (RTEs) and CD103+ T cells (mostly gut-experienced) and the role of Interleukin-(IL)-7 and IL-7 receptor (CD127)-expressing T cells in thymectomized patients compared to young and old healthy controls. Results Decreased proportions of naive and CD31 + CD8+ T cells were demonstrated after thymectomy, with higher proliferative activity of CD127-expressing T cells and significantly shorter relative telomere lengths (RTLs) and lower T cell receptor excision circles (TRECs). Increased circulating CD103+ T cells and a skewed T cell receptor (TCR) repertoire were found after thymectomy similar to elderly persons. Naive T cells were influenced by age at thymectomy and further decreased by CMV. Conclusions After childhood thymectomy, the immune system demonstrated constant efforts of the peripheral CD8+ T cell compartment to maintain homeostasis. Supposedly it tries to fill the void of RTEs by peripheral T cell proliferation, by at least partly IL-7-mediated mechanisms and by proportional increase of circulating CD103+ T cells, reminiscent of immune aging in elderly. Although other findings were less significant compared to healthy elderly, early thymectomy demonstrated immunological alterations of CD8+ T cells which mimic features of premature immunosenescence in humans