Graft-versus-Host Disease: Local Maintenance by Tissue Resident Progenitor T cells

University Of Pittsburgh At Pittsburgh, Pittsburgh PA

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Abstract

Abstract Allogeneic hematopoietic stem cell transplantation (alloSCT) can be a curative therapy for hematologic malignancies and inherited and acquired disorders of blood cells. Alloreactive graft T cells mediate the graft-vs- leukemia (GVL) effect and promote hematopoietic engraftment. However, they also attack normal host tissues causing graft-vs-host disease (GVHD). A central goal of alloSCT research has been to discover methods of minimizing and treating established GVHD with relative sparing of GVL and anti-pathogen immunity. This has been a challenge as most GVHD therapies target basic T cell functions. Development of more specific approaches will require a better understanding of GVHD biology. We considered the question of how GVHD is maintained once established. One possibility is that GVHD is sustained by the continuous generation of alloreactive effector T cells (Teff) in secondary lymphoid tissues (SLT), which then traffic to GVHD target tissues via blood. Alternatively, once tissues are seeded with alloreactive T cells, GVHD is maintained locally without significant input from SLT-derived T cells. A challenge to either model is that chronic alloantigen stimulation induces T cell exhaustion. We found through analysis of T cell clones in a CD4+ T cell receptor transgenic (TCR Tg; “TS1” T cells) GVHD model and through parabiosis of mice with GVHD induced by congenic TS1 cells or polyclonal CD4 and CD8 cells, that once established, GVHD is dominantly maintained locally within tissues with only a small ongoing contribution from blood-derived alloreactive T cells. We identified a tissue- resident Tcf7-expressing (protein is TCF-1) progenitor-like T cell subset (Tpro) in all tissues that we believe is critical for intratissue GVHD maintenance. These cells share features with TCF-1+ “progenitor exhausted” (Tpex) CD8+ T cells described in chronic viral infections and in anti-tumor responses. Tpex develop in the setting of sustained antigen stimulation (also the case with GVHD) and are dependent upon the transcription factor TOX, which we found to be upregulated in alloreactive T cells. Taken together, our data support a model wherein GVHD begins as a systemic immune response initiated by alloreactive T cell clones distributed from SLTs, which morphs into a systemic disease that is the sum of locally maintained intratissue T cells responding to continued local antigen exposure. Tissue-resident alloreactive Tpex would be ideal targets for GVHD prevention (by blocking their formation) and treatment (impair Tpex once formed). Achieving these objectives requires a detailed and mechanistic understanding of alloreactive Tpex/Tpro development and of the extrinsic signals and transcription factors that govern their survival, self-renewal, and differentiation into Teff. We will rigorously test the role of Tcf7 and Tcf7+ cells by inducibly deleting Tcf7 from T cells after GVHD is established. We will fate- map Tcf7-expressing cells using Tcf7-ERT2cre transgenic mice and perform genomic analysis on Tpro and their immediate Teff progeny. We will test the role of TOX using TOX-/- T cells and the role of antigen by varying antigen exposure. We will apply these techniques in the TS1 TCR Tg model and a polyclonal GVHD system.