Biology subjects

Keslar, K. S.

Publications and source records attributed to Keslar, K. S..

3 recordsLinked to original sources

bioRxiv2026

NK Cells Effectively Mediating Antibody-Mediated Kidney Allograft Rejection Requires a Specific Activation Receptor and Graft Expression of the Ligand

Acute antibody-mediated rejection (aABMR) is an important cause of clinical kidney graft injury and failure. Transcripts associated with NK cell activation in graft biopsies are diagnostic of aABMR, but mechanisms underlying NK cell activation during ABMR remain poorly understood. In contrast to the long-term (> 60 days) survival of complete MHC-mismatched kidney allografts in wild type C57BL/6 mice, B6.CCR5-/- recipients develop high titers of donor-specific antibody (DSA) with allograft rejection between days 18 to 28 post-transplant. This has allowed investigation of mechanisms underlying NK cell activation within kidney allografts during aABMR. DSA titers first became detectable in B6.CCR5-/- (H-2b) recipients of A/J (H-2a) kidney allografts at day 8 and peaked on day 15 post-transplant and was accompanied by a parallel increase in mRNA levels of Rae-1e, a ligand for the NK cell activation receptor NKG2D. A/J kidneys in B6.CCR5-/-NKG2D-/- recipients and A/J.Rae-1e-/- kidneys in B6.CCR5-/- recipients survived >60 days, despite high serum DSA levels. Flow cytometric analysis of allograft infiltrating cells in B6.CCR5-/- recipients on day 15 post-transplant revealed inflammatory monocyte and NK cell infiltration and NK cell activation to proliferate and express CD107a, a marker of cytotoxic function. These features of aABMR were absent or markedly reduced by recipient NKG2D- or donor graft Rae-1e-deficiency. These findings suggest that interference with expression of allograft Rae-1e or recipient NK cell NKG2D abrogates aABMR despite persistently high DSA levels and that aABMR requires coordination between infiltrating NK cell and inflammatory monocyte activation within the kidney allograft.

immunology↗

bioRxiv2025

NK cell allorecognition shapes reprogramming of neutrophils infiltrating heart allografts

BackgroundRecent developments in neutrophil biology have demonstrated that neutrophils are phenotypically and functionally heterogeneous. Tissue microenvironments dictate changes in neutrophil cell states in infection and cancer, but little is known about how alloimmune responses or solid organ transplantation influence neutrophil heterogeneity and plasticity. MethodsHere, we used the murine heterotopic heart transplant model in conjunction with high dimensional flow cytometry and transcriptome analysis to interrogate how the alloimmune response and microenvironment of a transplanted organ influence neutrophil subset differentiation and plasticity. Complete MHC mismatched A/J (H2a) or syngeneic B6 (H2b) hearts were transplanted to C57BL/6 or B6 background genetically modified recipients. ResultsWe uncovered striking differences between neutrophils infiltrating complete MHC mismatched allografts and syngeneic isografts. Bone marrow neutrophil development was highly skewed towards an immature, interferon stimulated gene (ISG)+ subset (marked by IFIT1 expression) early after transplant in both allo- and iso-graft recipients. ISG+ neutrophils were also the dominant population in the peripheral blood of both recipient groups. In contrast, neutrophils maintained the ISG+ phenotype after infiltrating an allograft but appeared to turn off this program upon infiltrating an isograft. The heart graft microenvironment imposed additional reprogramming independent of donor-recipient mismatch, as neutrophils from both allo- and iso-grafts were skewed towards a mature, aged and proangiogenic dcTRAIL-R1+ phenotype. Interestingly, while the existing literature indicates that IFIT1-expressing ISG+ neutrophils and proangiogenic dcTRAIL-R1+ neutrophils are distinct subsets, we identified a novel IFIT1+ dcTRAIL-R1+ hybrid population that is highly enriched in allografts. Mechanistically, NK cell-mediated innate allorecognition drives this early intra-allograft specific neutrophil phenotypic programing. ConclusionsThese findings provide novel insights into the innate immune allorecognition-mediated regulation of the plasticity of recently described key neutrophil subsets and will enable specific targeting to neutralize detrimental neutrophil subsets and enhance solid organ transplant outcomes.

immunology↗

bioRxiv2025

Inhibition of De Novo Autoantibody Production Attenuates Chronic Antibody-Mediated Rejection of Kidney Allografts Despite Maintenance of High Donor-Specific Antibody Titers

Acute and chronic antibody mediated rejection (ABMR) continues to decrease clinical kidney graft function and survival. Dysregulated donor-specific antibody (DSA) responses are induced in B6.CCR5-/- recipients of complete MHC-mismatched A/J kidney allografts with NK cells playing a critical role in the acute ABMR. We tested the role of neutrophils in ABMR by transplanting A/J kidneys to CCR5-/- mice with a deletion in the neutrophil serine protease cathepsin G. Whereas B6.CCR5-/- recipients rejected all kidney allografts between days 18-25, 70% of allografts survived beyond day 60 in B6.CCR5-/-cG-/- recipients. At days 15-17 post-transplant DSA titers in B6.CCR5-/-cG-/- recipients were 24.3-fold higher than those in wild-type C57BL/6 allograft recipients. Allografts from B6.CCR5-/-cG-/- recipients on days 45 and 60 had typical characteristics of chronic graft injury including interstitial collagen deposition and peri-glomerular fibrosis that was accompanied by a fibrogenic transcript signature and late post-transplant production of autoantibodies to many targets, including structural proteins including collagen IV and fibronectin. Depletion of B cells at the time DSA peak titers were achieved on day 14 post-transplant decreased serum autoantibodies levels, the kidney allograft fibrogenic transcript signature, and the chronic kidney allograft injury, despite maintenance of the high DSA titers. These results indicate a critical role for neutrophil cathepsin G during acute ABMR of kidney allografts and in its absence, DSA induced late appearance of autoantibodies mediating development of chronic kidney allograft injury.

immunology↗