Autoreactive cytotoxic T lymphocytes require target tissue stimulus to acquire cytotoxic effector capacity. (83.2)

Abstract

Abstract Cytotoxic T lymphocytes (CTL) are required for the development of autoimmune diseases such as type 1 diabetes. CTL are first activated in lymph nodes (LN) draining target tissue and then concentrate as fully differentiated CTL in the target tissue. We have studied the need for further stimulation of CTL after LN activation and the importance of APCs and the target tissue itself in CTL differentiation. Naïve CFSE-labeled pancreatic β cell specific 8.3-TCR transgenic CD8+ T cells were transferred into NOD mice. Autoreactive CTL proliferated and acquired limited expression of GranzymeB and IFNγ, signatures of cytotoxicity, in the pancreatic LN. CTLs in the islets had proliferated further and acquired higher expression of GzmB and IFNγ. This increased differentiation appeared to take place in the islet because expression of GzmB and IFNγ in CFSE-labeled T cells was similar in peripheral blood and PLN and T cells prevented from migrating from the PLN by FTY720 did not have increased cytotoxic differentiation. Reducing pancreatic β cell antigen presentation affected CTL proliferation but had little effect on differentiation. Increasing the density of antigen on APCs also had more impact on proliferation than differentiation. The data provide in vivo support for a signal required for CTL differentiation, in addition to TCR ligation and co-stimulation, which is produced in the inflamed target tissue. This suggests the target tissue is the critical location for CTL differentiation.