Immune regulatory receptors expressed on NK cells in type 1 diabetes.

Abstract

Abstract Auto-reactive T cells specific to islet antigens contribute to the onset of type 1 diabetes (T1D), yet NK cells may also play a role in disease onset and progression. Mouse models suggest a dual role for NK cells in disease onset and progression while human studies have found deficiencies in NK number and function. However, human studies are confounded by variability in cohorts (pre-T1D, recent onset, long-standing T1D) and more phenotypic and functional analysis as has been performed in murine studies. In our initial studies, we characterized activation and inhibitory markers on NK cells of longstanding T1D (n=5) as compared to healthy controls (n=6). NK cells from the same sample were then compared to known T cell phenotypes. PBMC were analyzed by flow cytometry for markers of T and NK cells (CD45RA, CCR7, CD56, CD4 and CD8), immune regulation (PD1, KLRG1, TIGIT and CD57) and activation (CD69 and CD25). Results showed that there was a significant elevation of T cells but a decrease of NK subsets (CD56dim and bright) in T1D compared to healthy controls. Both CD57+ and CD57+TIGIT+ NK cells were significantly reduced in T1D, implying a more immature and less regulatory phenotype or more activated phenotype. In the same subjects, both CD4 and CD8 memory T cell populations expressing PD1 were significantly lower in T1D than in healthy controls. Moreover, the CD8 EMRA (CCR7− CD45RA+) T cells exhibited decreased KLRG1, TIGIT and CD57 expression. Taken together, these findings revealed a skewing of NK cell subsets in T1D. Further functional characterization of both NK and T cells in the same sample may lead to identification of biomarkers for T1D.