Enhancing alloreactivity does not restore GVHD induction but augments skin graft rejection by CD4+ effector memory T cells

Graft-versus-host disease (GVHD) caused by donor T cells attacking recipient tissues is a major cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation (alloSCT). Studies have shown that effector memory T (T-EM) cells do not cause GVHD but are capable of immune functions post-transplant, including graft-versus-leukemia (GVL) effects, but the reasons for this are unclear. In mice, the T-EM pool may have a less diverse T-cell receptor (TCR) repertoire than naive T (T-N) cells with fewer alloreactive clones. We therefore tested whether enhancing the alloreactivity of T-EM cells would restore their ability to cause GVHD. In an MHC-matched system, alloreactive T-EM cells were created by transferring GVHD effector cells into syngeneic recipients and allowing conversion to T-EM cells. Upon retransfer to freshly transplanted recipients, these cells caused only mild GVHD. Similarly, in an MHC-mismatched system, T-EM cells with a proven increased precursor frequency of alloreactive clones only caused limited GVHD. Nonetheless, these same cells mounted strong in vitro alloresponses and caused rapid skin graft rejection. T-EM cells created from CD4(+) T cells that had undergone lymphopenia-induced proliferation (LIP) also caused only mild GVHD. Our findings establish that conversion to T-EM cells significantly reduces GVHD potency, even in cells with a substantially enhanced alloreactive repertoire.