Funding: 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.
Selective Targeting of Human Alloresponsive CD8+ Effector Memory T Cells Based on CD2 Expression
Version of Record online: 10 NOV 2010
©2010 The Authors Journal compilation©2010 The American Society of Transplantation and the American Society of Transplant Surgeons
American Journal of Transplantation
Volume 11, Issue 1, pages 22–33, January 2011
How to Cite
Lo, D. J., Weaver, T. A., Stempora, L., Mehta, A. K., Ford, M. L., Larsen, C. P. and Kirk, A. D. (2011), Selective Targeting of Human Alloresponsive CD8+ Effector Memory T Cells Based on CD2 Expression. American Journal of Transplantation, 11: 22–33. doi: 10.1111/j.1600-6143.2010.03317.x
- Issue online: 30 DEC 2010
- Version of Record online: 10 NOV 2010
- Received 15 May 2010, revised 03 September 2010 and accepted for publication 19 September 2010
- co-stimulation blockade;
- memory CD8 T cells
Costimulation blockade (CoB), 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 have recently shown that the CD2-specific fusion protein alefacept controls costimulation blockade-resistant allograft rejection in nonhuman 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 nonhuman primate data provide a rationale for translation of an immunosuppression regimen pairing alefacept and belatacept to human renal transplantation.