Direct Expansion of Functional CD25+ CD4+ Regulatory T Cells by Antigen-processing Dendritic Cells

Abstract

An important pathway for immune tolerance is provided by thymic-derived CD25+ CD4+ T cells that suppress other CD25− autoimmune disease–inducing T cells. The antigen-presenting cell (APC) requirements for the control of CD25+ CD4+ suppressor T cells remain to be identified, hampering their study in experimental and clinical situations. CD25+ CD4+ T cells are classically anergic, unable to proliferate in response to mitogenic antibodies to the T cell receptor complex. We now find that CD25+ CD4+ T cells can proliferate in the absence of added cytokines in culture and in vivo when stimulated by antigen-loaded dendritic cells (DCs), especially mature DCs. With high doses of DCs in culture, CD25+ CD4+ and CD25− CD4+ populations initially proliferate to a comparable extent. With current methods, one third of the antigen-reactive T cell receptor transgenic T cells enter into cycle for an average of three divisions in 3 d. The expansion of CD25+ CD4+ T cells stops by day 5, in the absence or presence of exogenous interleukin (IL)-2, whereas CD25− CD4+ T cells continue to grow. CD25+ CD4+ T cell growth requires DC–T cell contact and is partially dependent upon the production of small amounts of IL-2 by the T cells and B7 costimulation by the DCs. After antigen-specific expansion, the CD25+ CD4+ T cells retain their known surface features and actively suppress CD25− CD4+ T cell proliferation to splenic APCs. DCs also can expand CD25+ CD4+ T cells in the absence of specific antigen but in the presence of exogenous IL-2. In vivo, both steady state and mature antigen-processing DCs induce proliferation of adoptively transferred CD25+ CD4+ T cells. The capacity to expand CD25+ CD4+ T cells provides DCs with an additional mechanism to regulate autoimmunity and other immune responses.

Impaired regulatory T cell function in germ‐free mice

“…Interactions with the microbiota may provide a constant activation of T cells and induce continuous production of IL-2 by nonregulatory T cells as originally proposed by Papiernik et al [46]. IL-2 has proven crucial for the expansion and survival of Treg [47,48]. This concept is further supported by the observation that mice deficient of IL-2 develop colitis and autoimmune manifestations [46,[49][50][51].…”

“…Studies have shown that TLR-activated DC can reverse Treg anergy, suggesting that this could override suppression and permit protective immunity towards pathogens [52,53]. However, it has been demonstrated that Treg proliferation is transient, that Treg can return to their anergic and suppressive state, and that the proliferation expands the Treg population [47]. Other studies have reported that CD4 + T cells [54] and CD4 + CD25 + express several TLR and can be activated by LPS [55], which suggests a more direct influence of bacteria or bacterial products on Treg.…”

CD40/CD40L interaction regulates CD4+CD25+ T reg homeostasis through dendritic cell‐produced IL‐2

“…Due to the possible role of DC in sustaining T reg proliferation [10] we tested whether BM-derived DC from CD40KO differ from those of BALB/c mice in such function. T reg proliferation was 60% less when Ab to CD3 was presented by mature DC from CD40KO than wt mice (Fig.…”

Immunological mechanisms and clinical implications of regulatory T cell deficiency in a systemic autoimmune disorder: Roles of IL‐2 versus IL‐15

“…In agreement with this, importantly, we showed that such a defect in the MRL/lpr DC function could be fully restored by exogenous IL-2. IL-2 has been shown to be essential in the Treg induction by DC in various systems, both in an antigen-specific and nonspecific manner [50][51][52], although different findings were also reported [53]. It remains to be determined as to whether the T cells upon stimulation by the DC [51], or DC themselves, or both of the cell types together, could be the direct source of IL-2.…”

“…IL-2 has been shown to be essential in the Treg induction by DC in various systems, both in an antigen-specific and nonspecific manner [50][51][52], although different findings were also reported [53]. It remains to be determined as to whether the T cells upon stimulation by the DC [51], or DC themselves, or both of the cell types together, could be the direct source of IL-2. In addition, DC can also produce IL-15 [48,49,54], but whether or not and how this cytokine is involved in Treg induction is still to be clarified [53,55].…”