An obligate cell-intrinsic function for CD28 in Tregs

Abstract

Tregs expressing the transcription factor FOXP3 are critical for immune homeostasis. The costimulatory molecule CD28 is required for optimal activation and function of naive T cells; however, its role in Treg function has been difficult to dissect, as CD28 is required for thymic Treg development, and blockade of CD28-ligand interactions has confounding effects in trans on nonregulatory cells. To address this question, we created Treg-specific Cd28 conditional knockout mice. Despite the presence of normal numbers of FOXP3 + cells, these animals accumulated large numbers of activated T cells, developed severe autoimmunity that primarily affected the skin and lungs, and failed to appropriately resolve induced experimental allergic encephalomyelitis. This in vivo functional impairment was accompanied by dampened expression of CTLA-4, PD-1, and CCR6. Disease occurrence was not due to subversion of Cd28-deficient Tregs into pathogenic cells, as complementation with normal Tregs prevented disease occurrence. Interestingly, in these "competitive" environments, Cd28-deficient Tregs exhibited a pronounced proliferative/survival disadvantage. These data demonstrate clear postmaturational roles for CD28 in FOXP3 + Tregs and provide mechanisms which we believe to be novel to explain how interruption of CD28-ligand interactions may enhance immune responses independent of effects on thymic development or on other cell types.

Abatacept Inhibition of T Cell Priming in Mice by Induction of a Unique Transcriptional Profile That Reduces Their Ability to Activate Antigen‐Presenting Cells

“…Consistent with our findings, CD28 has previously been shown to play a significant role in Treg cell generation and function (46,47). Indeed, T cells from CD28-deficient mice failed to generate inducible Treg cells, which was attributed to a lack of T cell IL-2 production.…”

Selective blockade of CD28 on human T cells facilitates regulation of alloimmune responses

“…It is important to bear in mind that there are controversial findings regarding the function of Tregs in the absence of CD28 signals. Zhang and colleagues have demonstrated that Treg-specific CD28 conditional KO mice develop severe autoimmunity and that CD28-deficient Tregs lose suppressive function (36). Conversely, Poirier and colleagues have shown that selective blockade of CD28 costimulation promotes Treg suppression in a nonhuman primate model (37).…”

CD45 ligation expands Tregs by promoting interactions with DCs

“…Peripheral homeostasis is dependent on antigen presentation by DCs, since Treg number and HP are reduced when DCs lack MHC class II (17). Moreover, CD28 is required to maintain HP and peripheral Treg numbers (16,(18)(19)(20). This is only partially attributable to decreased IL-2 production by Tconvs in the absence of CD28 (18).…”