T Cells from NOD-PerIg Mice Target Both Pancreatic and Neuronal Tissue

Authors:
Open Access
Publisher website
Google Scholar
Abstract
It has become increasingly appreciated that autoimmune responses against neuronal components play an important role in type 1 diabetes (T1D) pathogenesis. In fact, a large proportion of islet-infiltrating B lymphocytes in the NOD mouse model of T1D produce Abs directed against the neuronal type III intermediate filament protein peripherin. NOD-PerIg mice are a previously developed BCR-transgenic model in which virtually all B lymphocytes express the H and L chain Ig molecules from the intra-islet–derived anti-peripherin–reactive hybridoma H280. NOD-PerIg mice have accelerated T1D development, and PerIg B lymphocytes actively proliferate within islets and expand cognitively interactive pathogenic T cells from a pool of naive precursors. We now report adoptively transferred T cells or whole splenocytes from NOD-PerIg mice expectedly induce T1D in NOD.scid recipients but, depending on the kinetics of disease development, can also elicit a peripheral neuritis (with secondary myositis). This neuritis was predominantly composed of CD4+ and CD8+ T cells. Ab depletion studies showed neuritis still developed in the absence of NOD-PerIg CD8+ T cells but required CD4+ T cells. Surprisingly, sciatic nerve–infiltrating CD4+ cells had an expansion of IFN-γ− and TNF-α− double-negative cells compared with those within both islets and spleen. Nerve and islet-infiltrating CD4+ T cells also differed by expression patterns of CD95, PD-1, and Tim-3. Further studies found transitory early B lymphocyte depletion delayed T1D onset in a portion of NOD-PerIg mice, allowing them to survive long enough to develop neuritis outside of the transfer setting. Together, this study presents a new model of peripherin-reactive B lymphocyte–dependent autoimmune neuritis.
Funding Information
  • Juvenile Diabetes Research Foundation (3-PDF-2017-372-A-N)
  • National Institutes of Health (NIH), National Institute of Diabetes and Digestive and Kidney Diseases (DK46266)
  • NIH, Office of the Director (OD-020351)
  • JDRF (2018-568)
  • NIH, National Institute of Neurological Disorders and Stroke (NS054154)
  • NIH, Office of the Director (OD-020351)
  • NIH, National Cancer Institute (CA34196)

This publication has 41 references indexed in Scilit: