Peripheral tissues reprogram CD8+ T cells for pathogenicity during graft-versus-host disease

Abstract

Graft-versus-host disease (GVHD) is a life-threatening complication of allogeneic stem cell transplantation induced by the influx of donor-derived effector T cells (TE) into peripheral tissues. Current treatment strategies rely on targeting systemic T cells; however, the precise location and nature of instructions that program TE to become pathogenic and trigger injury are unknown. We therefore used weighted gene coexpression network analysis to construct an unbiased spatial map of TE differentiation during the evolution of GVHD and identified wide variation in effector programs in mice and humans according to location. Idiosyncrasy of effector programming in affected organs did not result from variation in T cell receptor repertoire or the selection of optimally activated TE. Instead, TE were reprogrammed by tissue-autonomous mechanisms in target organs for site-specific proinflammatory functions that were highly divergent from those primed in lymph nodes. In the skin, we combined the correlation-based network with a module-based differential expression analysis and showed that Langerhans cells provided in situ instructions for a Notch-dependent T cell gene cluster critical for triggering local injury. Thus, the principal determinant of TE pathogenicity in GVHD is the final destination, highlighting the need for target organ–specific approaches to block immunopathology while avoiding global immune suppression.

Unraveling the Mechanisms of Cutaneous Graft-Versus-Host Disease

“…In vitro polarized Th17 cells also induce greater acute GVHD of the skin when transferred to allo-HSCT recipient mice ( 50 ), akin to their pathogenic role in other autoimmune and skin inflammatory diseases, such as psoriasis ( 53 ), scleroderma ( 54 ), and lichen planus ( 55 ). In a murine model of acute GVHD where we tracked the evolution of effector T cell gene expression according to time and location, we recently showed that transcriptional profiles of CD8 + effector T cells in the epidermis were highly distinct from other GVHD sites (including the dermis) and did not readily conform to previously published Tc1 or Tc17 signatures ( 35 ). Taken together, these data suggest that there is substantial redundancy in the requirements for acute skin injury in GVHD and/or that the precise molecular mechanisms leading to pathogenicity do not segregate exclusively with the “classic” differentiation pathways.…”

“…(B) During acute GVHD, the local production of IFN-γ inducible chemokines in response to tissue injury promotes the recruitment of CXCR3 + alloreactive T cells into the skin ( 34 ). Upon in situ interaction with host-type Langerhans cells, alloreactive T cells are reprogramed to differentiate into pathogenic effector cells characterized by enhanced survival and generation of IFN-γ ( 35 ). Pathogenic T cells kill Lgr5 + epidermal stem cells ( 36 ), thus disabling normal repair mechanisms and epidermopoiesis; these effects are manifested by vacuolar degeneration and apoptosis of the basal and suprabasal epidermal cells, focal dermo-epidermal separation, and necrosis of the epidermis with denudation.…”

“…An extensive summary of the role of individual T cell subsets and cytokines in GVHD pathogenesis is beyond the scope of this discussion, but we refer readers to recent reviews by experts in the field ( 27 , 41 ). In murine experimental systems, no single T cell differentiation pathway can explain the full spectrum of tissue injury at all sites; plasticity and heterogeneity of early T cell effector programs ( 35 , 42 ), variation in housing conditions, clinical relevance of the mouse models employed ( 43 ), and the potential impact of immune suppressants that are used in the clinic ( 44 ) all complicate this issue further. In addition, experiments using genetic approaches to block differentiation down one pathway may distort the overall balance of differentiation across other subsets, making the results often difficult to interpret ( 45 ).…”

“…In human patients, the persistence of recipient-derived LC does not predict clinical or histological skin GVHD ( 76 ), although this does not exclude a role of this population is initiating inflammation. Using models of inducible depletion in mice, we have found that host LC can “instruct” local T cell pathogenicity in an MHC-mismatched model of allo-HSCT where local GVHD was triggered by local application of a toll-like receptor agonist ( 77 ) and in several independent models of MHC-matched, minor antigen mismatched allo-HSCT ( 35 ). Host LCs were not required for activation of CD8 + T cells within the draining lymph node or subsequent homing of effector cells to the epidermis.…”

“…Host LCs were not required for activation of CD8 + T cells within the draining lymph node or subsequent homing of effector cells to the epidermis. Instead, epidermal LC triggered pathogenic differentiation of T cells in situ , an effect that was linked to the expression of a pro-inflammatory gene cluster that was also conserved in human patients at the onset of acute GVHD ( 35 ). In contrast, another study using Langerin.DTA BMT recipients (a model in which recipients lack LC through their lifespan) found that skin GVHD was unaffected in the absence of LC ( 78 ).…”