Donor Allospecific CD44high Central Memory T Cells Have Decreased Ability to Mediate Graft-vs.-Host Disease

Abstract

Data from both animal models and humans have demonstrated that effector memory T cells (T EM ) and central memory T cells (T CM ) from unprimed donors have decreased ability to induce graft-vs-host disease (GVHD). Allospecific T EM from primed donors do not mediate GVHD. However, the potential of alloreactive T CM to induce GVHD is not clear. In this study, we sought to answer this question using a novel GVHD model induced by T cell receptor (TCR) transgenic OT-II T cells. Separated from OT-II mice immunized with OVA protein 8 weeks earlier, the allospecific CD44 high T CM were able to mediate skin graft rejection after transfer to naive mice, yet had dramatically decreased ability to induce GVHD. We also found that these allospecific CD44 high T CM persisted in GVHD target organs for more than 30 days post-transplantation, while the expansion of these cells was dramatically decreased during GVHD, suggesting an anergic or exhausted state. These observations provide insights into how allospecific CD4 + T CM respond to alloantigen during GVHD and underscore the fundamental difference of alloresponses mediated by allospecific T CM in graft rejection and GVHD settings.

The primacy of gastrointestinal tract antigen-presenting cells in lethal graft-versus-host disease

“…112 The latter defect in memory T cells seems to involve enhanced AICD and exhaustion/ anergy. 113,114 It is therefore intriguing to consider that this may reflect a differential sensitivity of memory T cells to recipient DC-invoked AICD, and this should be further investigated. In humans, mHA-reactive CD8 T cells exist with high frequency, primarily in the naïve T-cell subset.…”

Human Wnt/β-Catenin Regulates Alloimmune Signaling during Allogeneic Transplantation

“…Several lines of evidence suggested that CD44 hi and CD122 hi T cells do not induce GVHD [27][28][29]. Our data showed that a high proportion of CD8 + T cells from Cat-Tg mice are CD44 hi and CD122 hi and express higher levels of Eomes (IMP phenotype) [19].…”

Wnt/β-catenin regulates alloreactive T cells for the treatment of hematological malignancies

“…Several lines of evidence suggested that CD44 hi and CD122 hi T cells do not induce GVHD (36)(37)(38). Our data showed that a high proportion of CD8 + T cells from Cat-Tg mice are CD44 hi and CD122 hi and express higher levels of Eomes (IMP phenotype) (29).…”