Session Name: Concurrent Session: New Pathways in Allograft Rejection
Date: Tuesday, May 2, 2017
Session Time: 2:30pm-4:00pm
Presentation Time: 3:30pm-3:42pm
Memory T cells can be a formidable barrier to long-term, rejection-free allograft survival, particularly in the setting of costimulation blockade. Ongoing work in the field has focused on identifying new pathways that control memory T cell responses during transplantation. FcγRIIB, the only inhibitory Fcγ receptor, inhibits intracellular signaling via the ITIM located in its cytoplasmic region. FcγRIIB is known to be expressed by many immune cell types, including B cells, myeloid cells and granulocytes; however, the general consensus has been that T cells do not express this molecule. We found that FcγRIIB-/- mice exhibit increased costimulation blockade-resistant rejection relative to WT controls (MSTs of 20 and 33 days, respectively (P=0.0002)). To determine whether this increased rejection was due to enhanced donor-specific antibody, we analyzed recipient serum at day 20 post skin graft and found that DSA levels in FcγRIIB-/- animals were not increased relative to WT animals in the presence of CTLA-4Ig. Because these data suggested that enhanced B cell responsiveness does not underlie the increased rejection observed in FcγRIIB-/- animals, we queried whether FcγRIIB is expressed on T cells during alloimmunity. Surprisingly, we found that the majority of donor-reactive CD8+ effector T cells upregulated FcγRIIB following skin transplantation. We queried the function of this molecule on CD8+ T cells, and found that in vivo blockade of FcγRIIB led to a significant increase in the frequency of donor-reactive CD8+ T cells in the draining lymph node at day 14 post transplant (p<0.05). Intriguingly, FcγRIIB expression on pathogen-elicited CD8+ memory T cells was heterogeneous (LM-OVA- 27%, γ-Herpesvirus-OVA- 15% and polyoma-OVA virus- 12%). Memory T cells elicited via these distinct antigen challenges pose differential barriers to graft survival following skin graft rechallenge in the presence of costimulation blockade (CoB). Compellingly, we identified a positive correlation (r2=0.9943) between the MST and frequency of antigen specific CD8+ memory T cells that express FcγRIIB, suggesting that the presence of the FcγRIIB coinhibitory molecule on T cells may render them more susceptible to a CoB based regimen. Overall, these data suggest a novel mechanism by which the production of alloantibody may function as a negative feedback loop to prevent alloreactive CD8+ T cell activation, and raise the possibility of an innovative approach to controlling donor-reactive CD8+ memory T cells during transplantation.
CITATION INFORMATION: Morris A, Pinelli D, Liu D, Ford M. FcγRIIB-Mediated Coinhibition Attenuates Donor-Reactive CD8+ T Cell Responses. Am J Transplant. 2017;17 (suppl 3).
To cite this abstract in AMA style:Morris A, Pinelli D, Liu D, Ford M. FcγRIIB-Mediated Coinhibition Attenuates Donor-Reactive CD8+ T Cell Responses. [abstract]. Am J Transplant. 2017; 17 (suppl 3). https://atcmeetingabstracts.com/abstract/fcriib-mediated-coinhibition-attenuates-donor-reactive-cd8-t-cell-responses/. Accessed August 3, 2021.
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