The role of regulatory T cells in the pathogenesis of sepsis and its clinical implication

Abstract

Sepsis is denoted as a complex syndrome that results from a serious infection followed by amplified and dysregulated inflammatory response. The complex immune response associated with sepsis results in a high rate of morbidity and mortality, despite substantial basic science and clinical advances. Recently, accumulating evidence have demonstrated that regulatory T cells (Tregs) play important roles in suppression of immune response, as demonstrated by the number increase and functional enhancement following the onset of severe sepsis or septic shock. This article reviews recent advances in understanding the potential role of Tregs in the pathophysiology of septic response, as well as implications in the development of novel therapeutic strategies for improving the clinical outcome of patients with severe injury and subsequent septic complications.

FIG. 1.

Natural and induced Treg populations. It is well known that natural Tregs can express the cell surface marker CD25 and the transcriptional factor FOXP3. In the periphery the majority of natural Tregs constitutively express high levels of CD25, but a significant minority express low levels of CD25 (Fontenot and others ; Wan and Flavell 2005). Both populations are immunosuppressive, and both express Foxp3. Other populations of antigen-specific Tregs can be induced from induced CD4⁺CD25⁻ or CD8⁺CD25⁻ T cells in the periphery under the influence of semimature dendritic cells, IL-10, TGF-β, and possibly IFN-α. These inducible populations of Tregs include distinct subtypes of CD4⁺ T cell: CD4⁺CD25⁺ Tr, T_H3, and Tr1 cells. Additionally, Foxp3⁺CD8⁺ T cells or a subtype of these cells can produce IL-10 and have been called CD8⁺ T regulatory cells (Mills 2004). Treg, regulatory T cell; IL-10, interleukin-10; TGF-β, transforming growth factor-β; IFN-α, interferon-α; T_H3, T helper 3; Tr1, T regulatory 1.

FIG. 2.

Targets of Tregs and mechanisms underlying immunosuppression. T_Reg cells (natural Tregs) inhibit the proliferation of CD25⁻ T cells by multifactorial mechanisms including cell–cell contact. Natural Tregs express CTLA-4, which interacts with CD80 and/or CD86 on the surface of antigen-presenting cells, and this interaction delivers a negative signal for T cell activation. In addition, it has been demonstrated that secreted or cell surface TGF-β or IL-10 might play role in immunosuppression mediated by natural Tregs. Inducible populations of Tregs include T_R1 cells, T_H3 cells, and CD8⁺ Tregs, produce IL-10 and/or TGF-β. These immunosuppressive cytokines could directly inhibit the proliferation and cytokine formation of effector T cells, including T_H1 cells, T_H2 cells, and CD8⁺ cytotoxic T lymphocytes. Immunosuppressive function of these cytokines also performed through inhibiting the maturation and activation of antigen-presenting cells (Mills 2004). CTLA-4, cytotoxic T-lymphocyte antigen 4; T_R1, T regulatory 1; MHC, major histocompatibility complex; APC, antigen presenting cell; TCR, T cell receptor.