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

Abstract

Graft-vs.-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 cells (TEM) do not cause GVHD but are capable of immune functions post-transplant, including graft-vs.-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 TN with fewer alloreactive clones. We therefore tested whether enhancing the alloreactivity of TEM would restore their ability to cause GVHD. In an MHC-matched system, alloreactive TEM were created by transferring GVHD effector cells into syngeneic recipients and allowing conversion to TEM. Upon retransfer to freshly transplanted recipients, these cells caused only mild GVHD. Similarly, in an MHC-mismatched system, TEM 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 created from CD4 cells that had undergone lymphopenia-induced proliferation also caused only mild GVHD. Our findings establish that conversion to TEM significantly reduces GVHD potency, even in cells with a substantially enhanced alloreactive repertoire.

Memory lapses in graft‐versus‐host disease

“…Again, CD4 1 T cells were primed in vitro before resting in antigen-free RAG À/À mice to generate T EM cell populations. Similar to their findings with polyclonal populations [4], the transgenic T EM cell population induced only transient GVHD as compared with that induced by T N cells [21]. These data demonstrate that intrinsic defects in T EM cells are relevant to their failure to induce GVHD.…”

“…Under these circumstances, the lack of GVHD following transfer of T MP cells would reflect a lower precursor frequency for alloantigen. This hypothesis is tested directly by Mark and Warren Shlomchik and colleagues in their article published in this issue of European Journal of Immunology [4]. The authors reasoned that if the lack of allospecific precursors within the memory CD4…”

“…While this may be of lesser significance in self-limiting infections, it could be critical under conditions where antigen is present at very high levels [27]. Thus, differences in proliferation, effector cytokine generation or survival, could potentially explain the findings of the very recent studies of Mark and Warren Shlomchik and colleagues in which CD4 1 T EM cells induced only transient GVHD followed by resolution [4,21]. In contrast to GVHD, it is possible that CD4 1 T EM -cell responses do not need to be sustained or produce a full repertoire of effector cytokines for skin grafts to be rejected.…”

“…One would envisage that alloreactive effector populations would require continual replenishment as individual effector cells undergo rapid terminal differentiation and exhaustion or deletion. Yet, it is noteworthy that even after 5 wk after the development of GVHD, effector CD4 1 T cells can still induce virulent GVHD upon transfer to secondary recipients [4]. While new thymic emigrants continuously supply replacement effectors in chronic infections, this is less likely to be relevant in the context of GVHD where thymic injury shuts down the output of naïve cells [6].…”

“…Alternatively, failure to produce effector cytokines could reflect a more general reduction in the fitness of CD4 1 T EM relative to T N cells. This might be most relevant under conditions where initial antigen presentation is prolonged, as in the study reported in this issue of the European Journal of Immunology [4], where the donor CD4 1 T cells were isolated from mice developing GVHD. Antigen presentation beyond the initial expansion phase leads to a subsequent failure of rested memory cells to proliferate or produce cytokines upon re-encountering antigen, a defect linked to impaired Jun phosphorylation [25].…”