Poster Presentation CD1-MR1 Workshop 2025

Competition between KIR3DL3 and TMIGD2 is a checkpoint mechanism for γδ and CD8+ T cells (#162)

Laura Leaton 1 , Camilla Faoro 2 , Jennifer R Habel 3 , Laura V Islas 1 , Ana Campos Codo 1 , Samuel D Burciaga 1 , Katherine M Kichula 1 , Noah Cline 1 , Suraju Sadeeq 1 , Andrew Stahly 1 , Dallas Jones 1 , Yuan Tan 2 , Thi HO Nguyen 3 , Eva Zhang 3 4 , Britt Christensen 4 , Michael Verneris 1 , Adrie Van Bokhoven 1 , Mark Gerich 1 , Yuwen Zhu 1 , Richard P Tobin 1 , Kristine Kuhn 1 , Katherine Kedzierska 2 , Jamie Rossjohn 2 , Liyen Loh 1 , Paul J Norman 1
  1. University of Colorado Anschutz, Denver, CO, United States
  2. Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Monash, VIC, Australia
  3. Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia
  4. Department of Gastroenterology, Royal Melbourne Hospital, Melbourne, VIC, Australia

Whereas most of the polymorphic human killer-cell immunoglobulin-like receptors (KIR) modulate peripheral NK cell activities through interaction with HLA class I, KIR3DL3 is expressed by mucosal γδ and CD8 T cells and binds B7H7 (HHLA2). B7H7 is a B7 family ligand found on antigen presenting cells and epithelial cells in intestinal tissues. B7H7 also engages the costimulatory receptor TMIGD2 (CD28H) on naïve T cells in the periphery and tissue-resident T cells in intestinal tissue. Potentially drawing parallels with CD28/B7/CTLA4, the functional relationship of KIR3DL3, B7H7 and TMIGD2 remains undefined. We show that TMIGD2 and KIR3DL3 are co-expressed on intestinal T cells, and that these receptors compete for binding with their shared ligand B7H7. In peripheral blood and intestinal tissue from Crohn’s disease patients, we observe increased KIR3DL3 expression on γδ and CD8 T cells, and that TMIGD2 levels on these KIR3DL3+ T cells increase concurrently. We show this expression variation is not due to KIR3DL3 polymorphism and KIR3DL3 is expressed by CD8 and γδ T cells at similar frequencies to healthy donors. We also analyzed KIR3DL3 and TMIGD2 expression on T cells in the periphery of rheumatoid arthritis and spondyloarthritis patients and observed no differences in frequencies or expression of these molecules, suggesting specificity of KIR3DL3-TMIGD2 opposition in intestinal mucosa. Importantly, KIR3DL3-mediated inhibitory signaling overrides TMIGD2 co-stimulation, even during synchronous TCR engagement. Together, these findings define a previously unrecognized KIR3DL3-TMIGD2-B7H7 checkpoint axis that may contribute to the intestinal homeostasis and dysregulation during inflammation.