Researchers from the University of Pittsburgh have recently published an article demonstrating that progenitor-like T cells locally maintain graft-versus-host disease (GVHD) in affected tissues, independent of blood-derived T cells, in a mouse model. This is believed to be due primarily to tissue resident TCF-1+ T cells, which are preferentially engrafted, expanded, and differentiated into effectors on adoptive transfer. These findings, published in the journal Immunity, help improve our overall understanding of GVHD maintenance and progression and potentially allow for more targeted GVHD therapies.
The mechanism by which the alloreactive T cell response is initiated and maintained in GVHD is currently not well known. There are two main hypotheses for GVHD maintenance: that T cells are continually activated in secondary lymphoid tissues (SLTs) and recruited to tissues, and that T cells are maintained within tissues through inputs from blood-derived T cells. Since neither model can explain how GVHD is maintained despite T cell exhaustion, the authors performed detailed T cell clone analysis and parabiosis to answer this question.
To delineate this mechanism, the authors used T cell receptor (TCR) transgenic GVHD models and found that there was a gradual switch from early distribution of clones to tissues to a locally maintained GVHD response. Mathematical modelling of clonal frequencies suggested that clonal compositions in SLT and target tissues did not become more related, and that new T cells in a given tissue must be locally derived. These findings suggested that GVHD is maintained in target tissues by a subset of progenitor-like cells. The results from parabiosis experiments, which tracked miHA-reactive CD4+ and CD8+ T cells to determine the source of T cells, further demonstrated a local GVHD maintenance. Lastly, single cell RNA-seq (scRNA-seq) experiments identified a cluster of Tcf7 (TCF-1) expressing T cells which maintain effector cells in GVHD affected tissues. Taken together, these findings demonstrate that progenitor-like T cells maintain GVHD locally.
Sacirbegovic F, Günther M, Greco A, et al. Graft-versus-host disease is locally maintained in target tissues by resident progenitor-like T cells. Immunity. 2023;56(2):369-385.e6. http://doi.org/10.1016/j.immuni.2023.01.00
Tags: GVHD, Cellular therapy, Research, Graft versus host disease, graft, graft-versus-host disease, RNA, T cell, graft-versus-host