Pathophysiological characteristics of preproinsulin-specific CD8+ T cells in subjects with juvenile-onset and adult-onset type 1 diabetes: A 1-year follow-up study.

Abstract

Among the beta-cell associated antigens, preproinsulin (PPI) has been shown to play a key role in the pathogenesis of type 1 diabetes (T1D). PPI-specific autoreactive CD8+ T cells emerge early during beta-cell destruction and persist in peripheral circulation during diabetes progression. However, the influence of insulin therapy on phenotype of autoreactive CD8+ T cells in T1D including, juvenile-onset T1D (JOT1D), and adult-onset T1D (AOT1D) is not yet known. We followed the time course of PPI-specific CD8+ T cells in JOT1D and AOT1D subjects that achieved glycemic control after 1 year of insulin therapy, using major histocompatibility complex-I (MHC-I) dextramers by flow cytometry. At follow-up, PPI-specific CD8+ T cells could be detected consistently in peripheral blood of all T1D subjects. Proportion of PPI-specific effector memory (TEM ) subsets decreased, while central memory T (TCM ) cells remained unchanged in both groups. Expression of granzyme-B and perforin in PPI-specific CD8+ T cells also remained unchanged. Further, on analysis of B-chain and signal peptide (SP) specific CD8+ T cell responses separately, we again observed decrease in TEM subset in both the groups, while increase in naive (TN ) subset was observed in B-chain specific CD8+ T cells only. Our study shows that PPI-specific CD8+ T cells can be detected in both JOT1D and AOT1D subjects over a period of time with reliable consistency in frequency but variable pathophysiological characteristics. Insulin therapy seems to reduce the PPI-specific TEM subsets; however, the PPI-specific TCM cells continue to persist as attractive targets for immunotherapy.