OR2 Recipient NK cell receptor repertoire comprising activating KIR2DS5 and licensed KIR3DL1 is associated with improved chronic lung allograft dysfunction (CLAD) free survival when donor misses HLA-BW4 ligand

Abstract

Aim Alloimmune responses manifesting as chronic lung allograft dysfunction (CLAD) limit long-term survival of lung transplant. Natural killer (NK) cells expressing an inhibitory KIR (iKIR) recognizing self-HLA can be activated when confronted with allograft lacking a ligand for that iKIR. Here we investigated if allograft missing ligand for recipient iKIR that had a cognate HLA ligand would enhance CLAD-free survival. We also analyzed the role of recipient’s activating KIRs (aKIR) on CLAD-free survival. Methods Using luminex rSSO methods, KIR and HLA genes were typed for 263 lung transplant recipients and HLA genes were typed for all donors. CLAD was determined by date of FEV1 or FVC drop to KIR-HLA genotypes. Results Bx KIR genotype recipients (i.e., carrying more a KIR s) had higher median CLAD-free survival than those carrying AA genotypes (Fig. A). Recipients with all 5 B haplotype-associated a KIR s ( 2DS1, S2, S3, S5, 3DS1 ) had enhanced CLAD-free survival relative to those missing one or more of these a KIR s. Particularly, recipients carrying 2DS5 showed enhanced CLAD-free survivals than those missing 2DS5 (Fig. B). Further, CLAD-free survival was higher for recipients carrying KIR3DL1 + Bw4 when donors missing Bw4 ligand (Fig. C). Allografts missing relevant ligands for recipients carrying 2DL1 + C2, 2DL2/L3 + C1, and/or 3DL2 + A3/A11 pairs were not associated with differential survival. Recipients with 2DS5, 3DL1, and Bw4 receiving donors missing Bw4 ligand showed the longest CLAD-free survival (p = 0.01, 9.2 median survival years; Fig. D). Conclusions Recipient NK cells expressing aKIRs and/or licensed KIR3DL1 may respond and deplete donor-derived antigen presenting cells that do not express Bw4 ligand, and thus impair direct allorecognition pathways which in turn delay CLAD. Functional studies will be required to understand the mechanism of KIR-HLA interactions in protecting from CLAD.