Tolerance has its limits: how the thymus copes with infection

The thymus is required for T cell differentiation; a process that depends on which antigens are encountered by thymocytes, the environment surrounding the differentiating cells, and the thymic architecture. These features are altered by local infection of the thymus and by the inflammatory mediators that accompany systemic infection. Although once believed to be an immune privileged site, it is now known that antimicrobial responses are recruited to the thymus. Resolving infection in the thymus is important because chronic persistence of microbes impairs the differentiation of pathogen-specific T cells and diminishes resistance to infection. Understanding how these mechanisms contribute to disease susceptibility, particularly in infants with developing T cell repertoires, requires further investigation.We thank Joana Neves and Nadine Santos for critical reading of the manuscript. This work was supported by Portuguese Foundation for Science and Technology (FCT) grant PTDC/SAU-MII/101663/2008 and individual fellowships to CN-A and CN. SMB was supported by National Institutes of Health Grant R01 R56 AI067731

Therapeutic B cell depletion impairs adaptive and autoreactive CD4+ T cell activation in mice

CD20 antibody depletion of B lymphocytes effectively ameliorates multiple T cell-mediated autoimmune diseases through mechanisms that remain unclear. To address this, a mouse CD20 antibody that depletes >95% of mature B cells in mice with otherwise intact immune systems was used to assess the role of B cells in CD4+ and CD8+ T cell activation and expansion in vivo. B cell depletion had no direct effect on T cell subsets or the activation status of CD4+ and CD8+ T cells in naive mice. However, B cell depletion impaired CD4+ T cell activation and clonal expansion in response to protein antigens and pathogen challenge, whereas CD8+ T cell activation was not affected. In vivo dendritic cell ablation, along with CD20 immunotherapy, revealed that optimal antigen-specific CD4+ T cell priming required both B cells and dendritic cells. Most importantly, B cell depletion inhibited antigen-specific CD4+ T cell expansion in both collagen-induced arthritis and autoimmune diabetes mouse models. These results provide direct evidence that B cells contribute to T cell activation and expansion in vivo and offer insights into the mechanism of action for B cell depletion therapy in the treatment of autoimmunity

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