Self-Recognition Sensitizes Mouse and Human Regulatory T Cells to Low-Dose CD28 Superagonist Stimulation

Abstract

In rodents, low doses of CD28-specific superagonistic monoclonal antibodies (CD28 superagonists, CD28SA) selectively activate regulatory T cells (Treg). This observation has recently been extended to humans, suggesting an option for the treatment of autoimmune and inflammatory diseases. However, a mechanistic explanation for this phenomenon is still lacking. Given that CD28SA amplify T cell receptor (TCR) signals, we tested the hypothesis that the weak tonic TCR signals received by conventional CD4+ T cells (Tconv) in the absence of cognate antigen require more CD28 signaling input for full activation than the stronger TCR signals received by self-reactive Treg. We report that in vitro, the response of mouse Treg and Tconv to CD28SA strongly depends on MHC class II expression by antigen-presenting cells. To separate the effect of tonic TCR signals from self-peptide recognition, we compared the response of wild-type Treg and Tconv to low and high CD28SA doses upon transfer into wild-type or H-2M knockout mice, which lack a self-peptide repertoire. We found that the superior response of Treg to low CD28SA doses was lost in the absence of self-peptide presentation. We also tested if potentially pathogenic autoreactive Tconv would benefit from self-recognition-induced sensitivity to CD28SA stimulation by transferring TCR transgenic OVA-specific Tconv into OVA-expressing mice and found that low-dose CD28SA application inhibited, rather than supported, their expansion, presumably due to the massive concomitant activation of Treg. Finally, we report that also in the in vitro response of human peripheral blood mononuclear cells to CD28SA, HLA II blockade interferes with the expansion of Treg by low-dose CD28SA stimulation. These results provide a rational basis for the further development of low-dose CD28SA therapy for the improvement of Treg activity.

Unregulated antigen-presenting cell activation by T cells breaks self tolerance

“…In considering how Treg removal causes naive T cells to respond to self ligands, recent studies on superagonistic CD28SA mAb [which caused florid pathology as TGN1412 in a clinical trial (40)] are instructive. In particular, injection of CD28SA into mice was shown to elicit proliferation of normal CD4 T cells, in addition to Tregs, although only when CD4 cells maintained contact with MHCII + DCs (41). These findings imply that the covert tonic TCR signals that keep normal T cells alive in the lymphoid tissues (19,42) can become overt following CD28 ligation and drive the cells into division.…”

Superagonistic CD28 protects against renal ischemia injury induced fibrosis through a regulatory T-cell expansion dependent mechanism

“…The Treg expansion effect of CD28sa depended largely on the MHCII expression of antigen presenting cells [28]. Therefore, we also tested the percentage of MHCII + CD11c + dendritic cells (DCs) from day 7 after IRI injury in mice.…”