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

BE Anderson, AL Tang, Y Wang… - European journal of …, 2011 - Wiley Online Library
BE Anderson, AL Tang, Y Wang, M Froicu, D Rothstein, JM McNiff, D Jain, AJ Demetris
European journal of immunology, 2011Wiley Online Library
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 (TEM) 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 TEM pool may have
a less diverse T‐cell receptor (TCR) repertoire than naive T (TN) cells with fewer alloreactive …
Abstract
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 (TEM) 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 TEM pool may have a less diverse T‐cell receptor (TCR) repertoire than naive T (TN) cells with fewer alloreactive clones. We therefore tested whether enhancing the alloreactivity of TEM cells would restore their ability to cause GVHD. In an MHC‐matched system, alloreactive TEM cells were created by transferring GVHD effector cells into syngeneic recipients and allowing conversion to TEM cells. Upon retransfer to freshly transplanted recipients, these cells caused only mild GVHD. Similarly, in an MHC‐mismatched system, TEM 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. TEM cells created from CD4+ T cells that had undergone lymphopenia‐induced proliferation (LIP) also caused only mild GVHD. Our findings establish that conversion to TEM cells significantly reduces GVHD potency, even in cells with a substantially enhanced alloreactive repertoire.
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