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Alloantigen Affinity and CD4 Help Determine Severity of Graft-versus-Host Disease Mediated by CD8 Donor T Cells¹

Xue-Zhong Yu^2,*,, Michael H. Albert^3,* and Claudio Anasetti^4,*,

^* Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109; and Department of Medicine, University of Washington, Seattle, WA 98195

TCR affinity dictates T cell selection in the thymus and also has a high impact on the fate of peripheral T cells. Graft-vs-host disease (GVHD) is a pathological process initiated by activation of donor T cells after adoptive transfer into an allogeneic recipient. How TCR affinity affects the potential of alloreactive T cells to induce GVHD is unclear. Using alloreactive CD4⁺ and CD8⁺ TCR transgenic (Tg) T cells, GVHD models are presented that allow for the visualization of how CD8⁺ alloreactive T cells behave in response to alloantigens with different TCR affinity in the absence or presence of CD4 help. In a nonmyeloablative transplant model where GVHD lethality is due to marrow aplasia, alloreactive CD8⁺ TCR Tg T cells induced significantly more severe GVHD in the recipients that express an intermediate-affinity alloantigen than in the recipients that express a high-affinity alloantigen. In a myeloablative transplant model where GVHD lethality is due to epithelium injury, CD8⁺ TCR Tg cells were also more pathogenic in the recipients with an intermediate-affinity alloantigen than in those with a high-affinity alloantigen. The presence of alloreactive CD4⁺ TCR Tg cells enhanced the potential of CD8⁺ TCR Tg cells to cause GVHD in recipients with an intermediate-, but not with a high-, affinity alloantigen. These findings underscore that alloantigen affinity and CD4 help control the fate and pathogenicity of alloreactive CD8⁺ T cells in vivo.

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				Y. Liang, C. Liu, J. Y. Djeu, B. Zhong, T. Peters, K. Scharffetter-Kochanek, C. Anasetti, and X.-Z. Yu 2 integrins separate graft-versus-host disease and graft-versus-leukemia effects Blood, January 15, 2008; 111(2): 954 - 962. [Abstract] [Full Text] [PDF]