. 2013 Aug 2;4:208. doi: 10.3389/fimmu.2013.00208

Table 1.

Subclasses of CD4⁺ T cells with regulatory function.

(A) PRESENT TO CONTROL AUTOIMMUNITY IN NORMAL HOSTS

nT_reg produced in thymus and released into periphery, prevent activation of destructive autoimmune responses. Absence of nT_reg due to neonatal thymectomy (19), lack of IL-2, CD25, or FoxP3 (223) leads to widespread autoimmunity. Expression of CTLA4 is required for function of nT_reg (224). These cells will control low level immune responses, and suppress at a ratio of 1:1 with more aggressive immune responses (58) including fully allogeneic responses (57, 59). They inhibit antigen presenting cells by direct contact and act in peripheral lymphoid tissues not at sites of inflammation

Induced T_reg generated when antigen is presented in a non-inflammatory environment, when TGF-β is present in the absence of activated antigen presenting cells and inflammatory cytokines such as IL-1β and IL-6. This produces additional T_reg, that are antigen specific to prevent induction of autoimmune response, in situations where self antigen is released due to non-inflammatory tissue injury such as trauma, ischemia, or chemical injury of tissue as well as in normal tissue re-modeling and failed or incomplete apoptosis, reviewed (225). In these circumstances TGF-β produced to promote repair of tissue also induces iT_reg to prevent unwanted and unnecessary autoimmune responses. Their survival is ephemeral if there is repair of tissue, but they may be further activated if inflammation supervenes

Th3 and Tr1 cells produced in mucosal sites, in response to antigens that penetrate the mucosa. There is abundant IL-10 and IL-10 family of cytokines, as well as TGF-β at these sites, that promotes tolerance induction to normal mucosal flora and oral antigens to prevent local and unwanted immune responses and inflammation that would disrupt the mucosal integrity. They are essential to the preservation of mucosal integrity and act by production of TGF-β and IL-10 that in turn promotes induction of more Th1 and Tr1

(B) PRESENT AFTER ACTIVATION OF AN IMMUNE RESPONSE TO A SPECIFIC ANTIGEN

Antigen Activation of nT_reg by inflammatory immune responses with cytokines produced early after activation of effector CD4⁺ T cells. The best described is the effects of high concentrations of IL-2, inducing expansion of nT_reg in the presence of a specific antigen. IL-4 also can induce activation of antigen specific T_reg from nT_reg. Th1 and Th2 responses induce expansion of antigen specific T_reg, respectively called Ts1 and Ts2 cells, that control responses other that that of the inducing response. This contributes to polarization to one response, for example Th2 cytokine activated nT_reg inhibit Th1 and Th17 responses

Activation of antigen specific activated nT_reg by cytokines produced late in an ongoing immune response. This induces the T_reg to express cytokines and transcription factors of the activated Th cells, so the T_reg become Th-like and express the transcription factor and late cytokines of that Th lineage

Conversion of activated effector cells to regulatory cells

(i) Activated T_reg infecting activated T cells, via IL-35/IL-10 (226) or surface TGF-β (227 ) to a regulatory T cell phenotype and function

(ii) Persistent activation of effector lineage induces them to produce IL-10 and dampen their own response as was described some 20 years ago (228–230)