Costimulation blockade of the CD28 pathway in the form of CTLA4Ig is known to attenuate T cell dependent antibody responses. T follicular helper (Tfh) cells are a subset of CD4+ T cells that provide requisite help to B cells for generation of the humoral immune response. Tfh cells are dependent upon CD28 costimulation and several studies have implicated CTLA4 as a key regulator of their differentiation and function. CTLA4Ig blocks both the CD28 costimulatory and CTLA4 coinhibitory pathways, therefore selective CD28 blockade has the potential to suppress CD28-mediated Tfh immunity while leaving negative CTLA4-mediated signaling intact. We have demonstrated that selective CD28 blockade results in superior skin allograft survival compared to CTLA4Ig by improved inhibition of donor-specific T cell responses through the CTLA4-dependent upregulation of a coinhibitory molecule on CD8+ T cells. Similarly, altering the balance of costimulatory and coinhibitory signaling on CD4+ Tfh cells with selective CD28 blockade to favor negative CTLA4-mediated signals could result in improved suppression of the Tfh-mediated humoral response. Thus, we used a T cell receptor transgenic murine skin allograft model to test whether a selective CD28-specific domain antibody (dAb) exhibits better suppression of CD4+ Tfh cell-mediated alloimmunity. Flow cytometric analysis of donor-reactive CD4+Thy1.1+ T cells from graft-draining lymph nodes following skin transplantation revealed increased expression of CTLA4 on CXCR5+ Tfh cells compared to CXCR5- cells, with the greatest level of CTLA4 expression on polarized CXCR5+GL7+ germinal center (GC) Tfh cells. Analysis of endogenous and donor-specific CD4+Thy1.1+ T cells demonstrated a greater reduction in the frequency and number of CXCR5+PD1+ Tfh cells within both polyclonal and graft-specific compartments with selective CD28 blockade as compared to CTLA4Ig. There was also a greater reduction in CXCR5+PD1+GL7+ GC Tfh cells. Examination of the B cell compartment revealed a greater reduction in the frequency and number of endogenous B220+ B cells, and following repeat skin transplant improved inhibition of the secondary donor-specific IgG response with the CD28 dAb. Taken together, these findings suggest that selective CD28 blockade in the presence of intact CTLA4 signaling may lead to improved control of humoral alloimmunity through superior inhibition of donor-reactive Tfh cells following transplantation.

CITATION INFORMATION: Badell I, Liu D, Suchard S, Nadler S, Ford M. CTLA4 Negatively Regulates Donor-Reactive CXCR5+PD1+ T Follicular Helper Cell Responses Following Transplantation. Am J Transplant. 2016;16 (suppl 3).

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