Fas-Mediated Apoptosis Regulates the Composition of Peripheral αβ T Cell Repertoire by Constitutively Purging Out Double Negative T Cells

BACKGROUND: The Fas pathway is a major regulator of T cell homeostasis, however, the T cell population that is controlled by the Fas pathway in vivo is poorly defined. Although CD4 and CD8 single positive (SP) T cells are the two major T cell subsets in the periphery of wild type mice, the repertoire of mice bearing loss-of-function mutation in either Fas (lpr mice) or Fas ligand (gld mice) is predominated by CD4(-)CD8(-) double negative alphabeta T cells that also express B220 and generally referred to as B220+DN T cells. Despite extensive analysis, the basis of B220+DN T cell lymphoproliferation remains poorly understood. In this study we re-examined the issue of why T cell lymphoproliferation caused by gld mutation is predominated by B220+DN T cells. METHODOLOGY AND PRINCIPAL FINDINGS: We combined the following approaches to study this question: Gene transcript profiling, BrdU labeling, and apoptosis assays. Our results show that B220+DN T cells are proliferating and dying at exceptionally high rates than SP T cells in the steady state. The high proliferation rate is restricted to B220+DN T cells found in the gut epithelium whereas the high apoptosis rate occurred both in the gut epithelium and periphery. However, only in the periphery, apoptosis of B220+DN T cell is Fas-dependent. When the Fas pathway is genetically impaired, apoptosis of peripheral B220+DN T cells was reduced to a baseline level similar to that of SP T cells. Under these conditions of normalized apoptosis, B220+DN T cells progressively accumulate in the periphery, eventually resulting in B220+DN T cell lymphoproliferation. CONCLUSIONS/SIGNIFICANCE: The Fas pathway plays a critical role in regulating the tissue distribution of DN T cells through targeting and elimination of DN T cells from the periphery in the steady state. The results provide new insight into pathogenesis of DN T cell lymphoproliferation

The effector T cell response to influenza infection

Influenza virus infection induces a potent initial innate immune response, which serves to limit the extent of viral replication and virus spread. However, efficient (and eventual) viral clearance within the respiratory tract requires the subsequent activation, rapid proliferation, recruitment, and expression of effector activities by the adaptive immune system, consisting of antibody producing B cells and influenza-specific T lymphocytes with diverse functions. The ensuing effector activities of these T lymphocytes ultimately determine (along with antibodies) the capacity of the host to eliminate the viruses and the extent of tissue damage. In this review, we describe this effector T cell response to influenza virus infection. Based on information largely obtained in experimental settings (i.e., murine models), we will illustrate the factors regulating the induction of adaptive immune T cell responses to influenza, the effector activities displayed by these activated T cells, the mechanisms underlying the expression of these effector mechanisms, and the control of the activation/differentiation of these T cells, in situ, in the infected lungs

Deficient interleukin 2 activity in MRL/Mp and C57BL/6J mice bearing the lpr gene.

Spleen cells from MRL-lpr and B6-lpr mice have a marked defect in the ability to produce interleukin 2 (IL-2) in response to concanavalin A stimulation. This defect precedes the onset of clinical illness, increases with age, and eventually becomes virtually absolute. It is not due to cellular suppression of IL-2 production, nor does it reflect the presence of a soluble inhibitor of IL-2 activity. Failure to restore IL-2 production with macrophage-replacing factors, such as interleukin 1 and phorbol myristic acetate, suggests that IL-2 deficiency reflects a primary T cell defect rather than a macrophage defect. MRL-lpr and B6-lpr spleen cells also have an age-dependent reduction in IL-2 response that apparently results from a deficiency of cell surface receptors for IL-2. Congenic MRL-+/+ and B6-+/+ mice, which lack the lpr gene responsible for accelerated autoimmunity and lymphoproliferation, have normal IL-2 activity. These findings suggest that a defect in IL-2 activity may contribute to impaired immunoregulation in mice bearing the lpr gene. The absence of such a defect in MRL-+/+ and B6-+/+ mice further suggests that a single autosomal recessive gene is responsible for IL-2 deficiency