Selective Targeting of Human Alloresponsive CD8+ Effector Memory T Cells Based on CD2 Expression

• Type of Material: Article
• Authors: Denise Jennifer Lo, Emory University; T. A. Weaver, Emory University; L. Stempora, Emory University; Aneesh K Mehta, Emory University; Mandy L Ford, Emory University; Christian P Larsen, Emory University; Allan D Kirk, Emory University
• Language: English
• Date: 2011-01
• Publisher: Wiley: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: ©2010 The Authors Journal compilation ©2010 The American Society of Transplantation and the American Society of Transplant Surgeons
• Final Published Version (URL): http://onlinelibrary.wiley.com/doi/10.1111/j.1600-6143.2010.03317.x/abstract
• Title of Journal or Parent Work: American Journal of Transplantation
• ISSN: 1600-6135
• Volume: 11
• Issue: 1
• Start Page: 22
• End Page: 33
• Grant/Funding Information: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID; This work was funded in part by research grants from the National Institutes of Health (2P01AI044644-10, 1U01AI079223-01A1, 1U01AI077821-01), the Georgia Research Alliance, and the Atlanta Clinical and Translation Science Institute.
• Research Categories: Health Sciences, Medicine and Surgery

Abstract

Costimulation blockade, specifically CD28/B7 inhibition with belatacept, is an emerging clinical replacement for calcineurin inhibitor-based immunosuppression in allotransplantation. However, there is accumulating evidence that belatacept incompletely controls alloreactive T cells that lose CD28 expression during terminal differentiation. We recently have shown that the CD2-specific fusion protein alefacept controls costimulation blockade-resistant allograft rejection in non-human primates. Here, we have investigated the relationship between human alloreactive T cells, costimulation blockade sensitivity and CD2 expression to determine whether these findings warrant potential clinical translation. Using polychromatic flow cytometry, we found that CD8+ effector memory T cells are distinctly high CD2 and low CD28 expressors. Alloresponsive CD8+CD2hiCD28− T cells contained the highest proportion of cells with polyfunctional cytokine (IFNγ, TNF and IL-2) and cytotoxic effector molecule (CD107a and granzyme B) expression capability. Treatment with belatacept in vitro incompletely attenuated allospecific proliferation, but alefacept inhibited belatacept-resistant proliferation. These results suggest that highly alloreactive effector T cells exert their late stage functions without reliance on ongoing CD28/B7 costimulation. Their high CD2 expression increases their susceptibility to alefacept. These studies combined with in vivo non-human primate data provide a rationale for translation of an immunosuppression regimen pairing alefacept and belatacept to human renal transplantation.