In:
The Journal of Immunology, The American Association of Immunologists, Vol. 210, No. 1_Supplement ( 2023-05-01), p. 173.05-173.05
Abstract:
Transplant patients must remain on toxic immunosuppression for life, underscoring the need to identify immunotherapeutic targets that may facilitate transplant tolerance. We recently showed that kidney transplant recipients that remained stable following withdrawal of mainstay immunosuppression exhibited increased levels of the glycosphingolipid-catabolizing protein Gm2a, specifically in CD8 +T cells, compared to patients who went on to reject their allografts. While the role of Gm2a in lysosomal glycosphingolipid degradation in neurons is well known, little is known about Gm2a function in the immune system. To investigate this, we performed skin graft surgery in WT vs Gm2a −/−mice. Results show that Gm2a deficiency significantly increased allograft rejection relative to WT counterparts. Moreover, adoptive transfer of donor-reactive WT vs. Gm2a −/−CD8 +T cells into WT hosts resulted in increased accumulation of donor-reactive T cells and accelerated allograft rejection in recipients of Gm2a −/−CD8 +T cells as compared to recipients of WT CD8 +T cells. This increased accumulation was likely due to increased proliferation, as in vitro studies revealed enhanced proliferation of CTV-labeled Gm2a −/−vs. WT CD8 +T cells. Interestingly, Gm2a −/−CD8 +T cells exhibited increased K b/SIINFEKL tetramer staining and sustained TCR expression following antigen stimulation compared to WT CD8 +T cells. Finally, Gm2a −/−CD8 +T cells exhibited increased responsiveness to low dose and low-affinity peptide compared to WT cells. In conclusion, these results identify Gm2a as a novel, CD8 +T cell-intrinsic regulator of the T cell activation threshold that directly impacts CD8 +T cell-mediated allograft rejection. Supported by grants from NIH (R01AI164716)
Type of Medium:
Online Resource
ISSN:
0022-1767
,
1550-6606
DOI:
10.4049/jimmunol.210.Supp.173.05
Language:
English
Publisher:
The American Association of Immunologists
Publication Date:
2023
detail.hit.zdb_id:
1475085-5
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