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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. [ABSTRACT FROM AUTHOR]

The presence of FoxP3(+) regulatory T cells (Tregs) is necessary for control of deleterious immune responses in the steady state; however, mechanisms for maintaining the frequency and quality of endogenous Tregs are not well defined. In this study, we used in vivo modulators of the CD28 and CTLA4 pathways administered to intact mice to reveal mechanisms controlling the homeostasis and phenotype of endogenous Tregs. We demonstrate that expression of the negative costimulatory regulator CTLA4 on FoxP3(+) Tregs in vivo is a direct consequence of their rapid, perpetual homeostasis. Up-regulation of CTLA4 expression occurs only on FoxP3(+) Tregs undergoing extensive proliferation and can be abrogated by inhibiting the CD28 pathway, coinciding with a reduction in FoxP3(+) Treg proliferation and frequency. We further demonstrate that CTLA4 negatively regulates steady-state Treg homeostasis, given that inhibiting CTLA4 signaling with an anti-CTLA4 blocking Ab greatly enhances Treg proliferation and overall Treg frequency. Our findings provide new insight into the origin and role of CTLA4 expression on natural FoxP3(+) Tregs and reveal opposing effects of costimulation modulators on the steady-state level and quality of Tregs, with implications regarding their effects on endogenous Tregs in patients receiving immunotherapy.