Anti-TCRβ mAb Induces Long-Term Allograft Survival by Reducing Antigen-Reactive T Cells and Sparing Regulatory T Cells

Abstract

TCR specific antibodies may modulate the TCR engagement with antigen–MHC complexes, and in turn regulate in vivo T cell responses to alloantigens. Herein, we found that in vivo administration of mAbs specific for mouse TCRβ (H57–597), TCRα or CD3 promptly reduced the number of CD4+ and CD8+ T cells in normal mice, but H57–597 mAb most potently increased the frequency of CD4+Foxp3+ Treg cells. When mice were injected with staphylococcal enterotoxin B (SEB) superantigen and H57–597 mAb, the expansion of SEB‐reactive Vβ8+ T cells was completely abrogated while SEB‐nonreactive Vβ2+ T cells remained unaffected. More importantly, transient H57–597 mAb treatment exerted long‐lasting effect in preventing T cell responses to alloantigens, and produced long‐term cardiac allograft survival (>100 days) in 10 out of 11 recipients. While Treg cells were involved in maintaining donor‐specific long‐term graft survival, T cell homeostasis recovered over time and immunity was retained against third party allografts. Moreover, transient H57–597 mAb treatment significantly prolonged survival of skin allografts in naïve recipients as well as heart allografts in skin‐sensitized recipients. Thus, transient modulation of the TCRβ chain by H57–597 mAb exhibits potent, long‐lasting therapeutic effects to control alloimmune responses.

Selective FcγR Co-engagement on APCs Modulates the Activity of Therapeutic Antibodies Targeting T Cell Antigens

“…Administration of staphylococcal enterotoxin B (SEB peptide) elicits an antigen-specific TCR (Vβ8 + ) T cell response in mice (Miyahara et al, 2012). This model provided an opportunity to evaluate the role of FcγR co-engagement by an anti-CTLA-4 mAb in non-tumor-bearing animals.…”

“…To test the importance of FcγRIV for the function of anti-CTLA-4, mice were concurrently injected with a single dose of FcγRIV-specific blocking mAb (glycosylated or deglycosylated clone 9E9, 200 μg) or hamster IgG isotype control (200 μg). Blood and/or spleens were collected at 0, 72, 144, or 240 hr post-treatment and analyzed as described (Miyahara et al, 2012). For mAb-mediated depletion of FoxP3 + Treg cells, C57BL/6 mice were treated with a single i.p.…”

TCR stimulation without co-stimulatory signals induces expression of “tolerogenic” genes in memory CD4 T cells but does not compromise cell proliferation

“…It would be interesting to know whether reduced sensitivity to TCR signaling promotes the expression of Egr2 and GRAIL. Memory CD8 + T cells are susceptible to peripheral tolerance (Kreuwel et al, 2002;Jellison et al, 2012), though memory T cell responses are resistant to co-stimulation blockade and anti-TCR mAb treatment (Miyahara et al, 2012). Defining the role of Egr2, GRAIL, and many other intracellular regulators in memory T cell responses is critical for inducing transplant tolerance and preventing autoimmunity.…”

“…To enrich alloreactive memory T cells, B6 mice were transplanted with BALB/c skin allografts. The method of Skin transplantation has been previously described (Miyahara et al, 2012). One month after OVA immunization or skin transplantation, the CD4 + CD44 high memory and CD4 + CD44 low naive T cells were isolated from spleens using a FACSAria cell sorter (Becton Dickinson, CA), and cultured in anti-CD3 coated plates for 24 h. RNA was extracted using the Qiagen RNeasy Mini Kit (Valencia, CA) and reverse-transcribed into cDNA (SABiosciences, Frederick, MD), followed by real time qPCR (QuantiFast Assay, Qiagen) analysis.…”

Reestablishing T Cell Tolerance by Antibody-Based Therapy in Type 1 Diabetes

“…Treg (Deng et al 2014;Miyahara et al 2012). Notably, anti-TCRb Ab induces considerably less cytokine release by T cells compared to anti-CD3 Ab.…”