Contributions
Abstract: S818
Type: Oral Presentation
Presentation during EHA23: On Saturday, June 16, 2018 from 11:30 - 11:45
Location: Room K1
Background
Acute graft-versus-host disease (GVHD) is a known risk factor for the later development of chronic GVHD. Although thymic injury during acute GVHD leads to the de novo generation of self-reactive T cells, the “two hit” hypothesis proposes that the additional loss of peripheral mechanisms is required for autoimmunity. Non-hematopoietic lymph node stromal cells (LNSC) provide a platform for peripheral tolerance by expressing and directly presenting tissue-restricted antigens (TRAs) to T cells.
Aims
The aim of this work was to test the hypothesis that alloreactive T cells could directly kill LNSC in the GVHD recipient, thus disrupting a critical mechanism for preventing injury by auto-aggressive donor T cells.
Methods
To test this concept, we used a clinically relevant model of MHC-matched, B6 female → B6 male bone marrow transplantation (BMT) where GVHD is induced by the co-transfer of anti-HY TCR-transgenic MataHari CD8+ T cells.
Results
We found that fibroblastic reticular cells (FRC), a LNSC subset identified as CD45-CD31-gp38+, were reduced ~15-fold in mice with GVHD whereas other LNSC, including lymphatic or blood endothelial cells were less affected. FRC injury was associated with a profound loss of type 3 innate lymphoid cells (ILC3). Consistent with injury to FRC, transcription of both Il-7 and Ccl19 genes was significantly reduced in LN stroma of mice with GVHD. Furthermore, the repertoire of putative TRAs expressed by FRC was also substantially reduced. To test the hypothesis that acute GVHD interferes with FRC capacity to express TRAs and induce peripheral tolerance, we exploited the iFABPtOVA model where truncated ovalbumin (tOVA) antigen is expressed by intestinal epithelial cells and ectopically by FRC; in the steady state, direct presentation of tOVA by FRC induces clonal elimination of antigen-specific T cells. Transfer of HY-specific T cells into iFABPtOVA male BMT recipient reduced intranodal tOVA expression by 15-fold compared to no GVHD controls. To test whether acute GVHD-mediated FRC damage impairs tolerance induction, 106 OT-I T cells (a surrogate for self-reactive T cells) were adoptively transferred to GVHD+ or GVHD- iFABPtOVA recipients at 6 weeks following BMT. Transferred OT-I T cells were efficiently tolerized and clonally deleted in GVHD- iFABPtOVA recipients. However, in GVHD+ iFABPtOVA, OT-I T cells were not eliminated, and a large number of IFNγ+ effector cells expanded in LN and intestinal epithelium, leading to severe weight loss and intestinal injury.
Conclusion
Taken together, our data demonstrate that acute GVHD reduces TRA display by FRC and induces loss of a critical peripheral tolerance mechanism that prevents expansion and pathogenicity of autoreactive T cells. These findings provide a potential mechanism to explain the link between acute GVHD and the succeeding autoimmunity observed in chronic GVHD.
Session topic: 22. Stem cell transplantation - Experimental
Keyword(s): Acute graft-versus-host disease, Autoimmunity, T cell, tolerance
Abstract: S818
Type: Oral Presentation
Presentation during EHA23: On Saturday, June 16, 2018 from 11:30 - 11:45
Location: Room K1
Background
Acute graft-versus-host disease (GVHD) is a known risk factor for the later development of chronic GVHD. Although thymic injury during acute GVHD leads to the de novo generation of self-reactive T cells, the “two hit” hypothesis proposes that the additional loss of peripheral mechanisms is required for autoimmunity. Non-hematopoietic lymph node stromal cells (LNSC) provide a platform for peripheral tolerance by expressing and directly presenting tissue-restricted antigens (TRAs) to T cells.
Aims
The aim of this work was to test the hypothesis that alloreactive T cells could directly kill LNSC in the GVHD recipient, thus disrupting a critical mechanism for preventing injury by auto-aggressive donor T cells.
Methods
To test this concept, we used a clinically relevant model of MHC-matched, B6 female → B6 male bone marrow transplantation (BMT) where GVHD is induced by the co-transfer of anti-HY TCR-transgenic MataHari CD8+ T cells.
Results
We found that fibroblastic reticular cells (FRC), a LNSC subset identified as CD45-CD31-gp38+, were reduced ~15-fold in mice with GVHD whereas other LNSC, including lymphatic or blood endothelial cells were less affected. FRC injury was associated with a profound loss of type 3 innate lymphoid cells (ILC3). Consistent with injury to FRC, transcription of both Il-7 and Ccl19 genes was significantly reduced in LN stroma of mice with GVHD. Furthermore, the repertoire of putative TRAs expressed by FRC was also substantially reduced. To test the hypothesis that acute GVHD interferes with FRC capacity to express TRAs and induce peripheral tolerance, we exploited the iFABPtOVA model where truncated ovalbumin (tOVA) antigen is expressed by intestinal epithelial cells and ectopically by FRC; in the steady state, direct presentation of tOVA by FRC induces clonal elimination of antigen-specific T cells. Transfer of HY-specific T cells into iFABPtOVA male BMT recipient reduced intranodal tOVA expression by 15-fold compared to no GVHD controls. To test whether acute GVHD-mediated FRC damage impairs tolerance induction, 106 OT-I T cells (a surrogate for self-reactive T cells) were adoptively transferred to GVHD+ or GVHD- iFABPtOVA recipients at 6 weeks following BMT. Transferred OT-I T cells were efficiently tolerized and clonally deleted in GVHD- iFABPtOVA recipients. However, in GVHD+ iFABPtOVA, OT-I T cells were not eliminated, and a large number of IFNγ+ effector cells expanded in LN and intestinal epithelium, leading to severe weight loss and intestinal injury.
Conclusion
Taken together, our data demonstrate that acute GVHD reduces TRA display by FRC and induces loss of a critical peripheral tolerance mechanism that prevents expansion and pathogenicity of autoreactive T cells. These findings provide a potential mechanism to explain the link between acute GVHD and the succeeding autoimmunity observed in chronic GVHD.
Session topic: 22. Stem cell transplantation - Experimental
Keyword(s): Acute graft-versus-host disease, Autoimmunity, T cell, tolerance