A repertoire-independent and cell-intrinsic defect in murine GVHD induction by effector memory T cells

Effector memory T cells (T-EM) do not cause graft-versus-host disease (GVHD), though why this is has not been elucidated. To compare the fates of alloreactive naive (T-N) or memory (T-M) T cells, we developed a model of GVHD in which donor T cells express a transgene-encoded TCR specific for an antigenic peptide that is ubiquitously expressed in the recipient. Small numbers of naive TCR transgenic (Tg) T cells induced a robust syndrome of GVHD in transplanted recipients. We then used an established method to convert TCR Tg cells to T-M and tested these for GVHD induction. This allowed us to control for the potentially different frequencies of alloreactive T cells among T-N and T-M, and to track fates of alloreactive T cells after transplantation. T-EM caused minimal, transient GVHD whereas central memory T cells (T-CM) caused potent GVHD. Surprisingly, T-EM were not inert: they, engrafted, homed to target tissues, and proliferated extensively, but they produced less IFN-gamma and their expansion in target tissues was limited at later time points, and local proliferation was reduced. Thus, cell-intrinsic properties independent of repertoire explain the impairment of T-EM, which can initiate but cannot sustain expansion and tissue damage. (Blood. 2011;118(23):6209-6219)