Foxp3⁺CD25⁺CD4⁺ natural regulatory T cells in dominant self‐tolerance and autoimmune disease

Abstract

Naturally arising CD25+ CD4+ regulatory T (Treg) cells, most of which are produced by the normal thymus as a functionally mature T-cell subpopulation, play key roles in the maintenance of immunologic self-tolerance and negative control of a variety of physiological and pathological immune responses. Natural Tregs specifically express Foxp3, a transcription factor that plays a critical role in their development and function. Complete depletion of Foxp3-expressing natural Tregs, whether they are CD25+ or CD25-, activates even weak or rare self-reactive T-cell clones, inducing severe and widespread autoimmune/inflammatory diseases. Natural Tregs are highly dependent on exogenously provided interleukin (IL)-2 for their survival in the periphery. In addition to Foxp3 and IL-2/IL-2 receptor, deficiency or functional alteration of other molecules, expressed by T cells or non-T cells, may affect the development/function of Tregs or self-reactive T cells, or both, and consequently tip the peripheral balance between the two populations toward autoimmunity. Elucidation of the molecular and cellular basis of this Treg-mediated active maintenance of self-tolerance will facilitate both our understanding of the pathogenetic mechanism of autoimmune disease and the development of novel methods of autoimmune disease prevention and treatment via enhancing and re-establishing Treg-mediated dominant control over self-reactive T cells.

Mechanisms of sepsis‐induced immunosuppression and immunological modification therapies for sepsis

“…Thereafter, Forkhead box protein 3 (Foxp3) was found to be expressed in CD4 + CD25 + T cells, and these cells were subsequently named Treg cells. Treg cells are central to the maintenance of immunological homeostasis and tolerance 33, 34. In septic patients, the percentages of circulating Treg cells are markedly increased, which presumably contributes to the occurrence of sepsis‐induced immunosuppression 35.…”

Importance of T Lymphocytes in Brain Injury, Immunodeficiency, and Recovery after Cerebral Ischemia

“…An important CD4 + T-cell subtype that accounts for B10% of all CD4 + T cells (Zouggari et al, 2009) and which expresses CD25 and the transcription factor Foxp3, is the regulatory T cell (T reg ; i.e., CD4 + CD25 + Foxp3 + cells). T reg cells act to limit the immune response and thus prevent autoimmune disorders (Sakaguchi et al, 2006) via their release of transforming growth factor-b and IL-10 (Liesz et al, 2009b). Figure 1 Potential actions of T lymphocytes in the brain following stroke.…”

In vitro generation of CD4+CD25+ regulatory cells from murine naive T cells

“…Indeed these cells are thought to prevent the activation and expansion of autoreactive T-cell clones that have escaped the negative selection in the thymus 1 . Tregs are generated in the thymus after the first days of postnatal life and then migrate into peripheral organs where they can prevent the activation of autoreactive T-cell clones.…”