Regulatory T cells play a role in T‐cell receptor CDR2 peptide regulation of experimental autoimmune encephalomyelitis

Abstract

Summary Eliciting T‐cell receptor (TCR) ‐specific responsiveness has been known to provide an effective autoregulatory mechanism for limiting inflammation mediated by T effector cells. Our previous use of TCR peptides derived from the CDR3 regions of a pathogenic TCR effectively reversed ongoing experimental autoimmune encephalomyelitis (EAE) in a humanized TCR transgenic model. In this study, we use the TCR BV8S2 CDR2 peptide in the non‐transgenic C57BL/6 EAE model to down‐regulate the heterogeneous TCR BV8S2+ MOG‐35‐55‐specific pathogenic T‐cell population and demonstrate successful treatment of EAE after disease onset. Suppression of disease was associated with reduced MOG‐35‐55‐specific and non‐specific T‐cell production of interleukin‐17a and interferon‐γ in the central nervous system, as well as reduced numbers of CD4+ and Foxp3+ T cells in the central nervous system. With the use of Foxp3‐GFP and Foxp3 conditional knockout mice, we demonstrate that the TCR CDR2 peptide treatment effect is dependent on the presence of Foxp3+ regulatory T cells and that regulatory T cell numbers are significantly expanded in the periphery of treated mice. Hence, TCR CDR2 peptide therapy is effective in regulating heterogeneous, pathogenic T‐cell populations through the activity of the Foxp3+ regulatory T cell population.

Therapeutic Effect of Anti-CD52 Monoclonal Antibody in Multiple Sclerosis and Its Animal Models Is Mediated via T Regulatory Cells

“…Because Moltedo et al (29) reported transient generalized lymphopenia restricted to peripheral, but not thymic, T cells at day 2 after DT administration, which subsequently had increased T cell activation by day 4, we would like to emphasize that our study determined T cell responses at day 9 after DT administration when lymphocyte counts have normalized. Although because of limited Treg numbers we did not demonstrate (31), to provide a proof of principle that anti-CD52 mAb treatment effect is dependent on the presence of Tregs. Because the anti-CD52mAb effect in DEREG 1 DTtreated mice is similar to, but not more severe than, in WT mice (30), it is possible that anti-CD52 mAb therapeutic effect is partially mediated independently of Tregs.…”

Human Transcriptome Array Analysis Identifies CDR2 as a Novel Suppressed Gene for Kawasaki Disease

“…Balamurugan et al indicated that the overexpression of the CDR2 gene plays an important role in repressing HIF-1 transactivation activity by interfer-ing with p300 recruitment in their study on solid tumors [35]. Buenafe et al also showed that T-cell receptor CDR2 peptide immunotherapy was effective in regulating pathogenic T-cells via the activity of the Foxp3(+) regulatory T-cells [33], which is consistent with our previous findings that IVIG therapy for KD results in increased expression of Treg-related FoxP3 [17]. Herein, we showed that the suppression of the CDR2 gene of leukocytes and its increase after IVIG administration may play a role in the pathogenesis of KD.…”

“…CDR2 is expressed in the central nervous system, and its ectopic expression in tumor cells of patients with gynecological malignancies is associated with paraneoplastic cerebellar degeneration [ 31 , 32 ]. Additionally, CDR2 can be detected in vascular smooth muscle cells of rats and humans [ 33 ]. Interestingly, CD8+cytotoxic T cells will fail to activate T cells expressing CDR2 in response to epithelial cells expressing CDR2 [ 34 ].…”