Controlling Autoreactivity of CD4 T Cells by Local Tolerance Induction

Journal of Immunology Research, Aug 2018

Irmgard FöRster

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Controlling Autoreactivity of CD4 T Cells by Local Tolerance Induction

Controlling Autoreactivity of CD4 T Cells by Local Tolerance Induction IRMGARD F(RSTER 0 0 alnstitute for Genetics, University of Cologne , Cologne , Germany *Corresponding author. Present address: Institut ftir Genetik, Weyertal 121, D-50931 K61n, Germany. - Minireview INTRODUCTION Autoimmune diseases are often caused by the inappropriate activation of CD4 T cells specific for peripheral self-antigens. Since these cells recognize their target antigens in the context of MHC class II molecules on the surface of specialized antigenpresenting cells (APC), the induction of immunity, or alternatively tolerance, of CD4 T cells depends on the release of antigens from peripheral tissues and uptake by APC. To study this process, transgenic mouse models have been established in which experimental self-antigens are expressed under the control of tissue-specific promoters. With the availability of T-cell-receptor (TCR)-transgenic mice specific for the respective antigen, the T-cell response toward such neo self-antigens can be followed directly during the development of the immune system (for review, see Himmerling et al., 1993; Kruisbeek and Amsen, 1996; Mondino et al., 1996) The transgenic mouse model described here has been originally established by D. Hanahan with the intention to study tissue-specific tumorigenesis following expression of a viral oncogene, the SV40 T antigen (Tag), under control of the rat insulin II gene promoter (RIP) (Hanahan, 1985) . Independent lines of RIP-Tag transgenic mice were later shown to mount characteristic immune responses toward Tag, depending on the onset and level of Tag expression during ontogeny (Adams et al., 1987) . Thus, RIP1Tag2 (abbreviated RT2) mice with embryonic onset of Tag expression were found to establish systemic tolerance toward Tag, whereas other lines of mice with delayed onset of Tag expression developed a spontaneous autoimmune response against their pancreatic/3 cells ( Skowronski et al., 1990 ; Jolicoeur et al., 1994; F6rster et al., 1995 ). With the aim of generating Tag-specific TCRtransgenic mice to study the mechanism of induction of tolerance versus autoimmunity in this system, we identified and cloned a MHC class II restricted Tagspecific TCR that was expressed on Tag-specific CD4 T cells isolated from pancreatic infiltrates of an autoimmune RIP1-Tag5 mouse ( F6rster et al., 1995 ). Genomic constructs encoding this Tag-specific TCR were injected into fertilized mouse oocytes and two independent lines of transgenic mice were obtained in which either a single copy of the TCR c-chain gene and two copies of the TCR/3-chain gene (TCR1 mice) or multiple copies of both TCR c and/3 (TCR2 mice) were cointegrated into the genome. With the help of an anti-idiotypic antibody specific for the transgenic TCR, it could be demonstrated that TCR1 mice expressed the transgenic receptor on no more than 0.5% of thymocytes and 10% of peripheral CD4 T cells, whereas the majority of peripheral T cells expressed endogenous TCR. In contrast, TCR2 mice carried the transgenic TCR on almost all thymocytes and 90% of peripheral T cells ( F6rster et al., 1995 ). The reason for this differential expression of the transgenic TCR in TCR1 versus TCR2 mice is presently unknown but most likely depends on position effects of the transgene integration site. ESTABLISHMENT OF PERIPHERAL TOLERANCE DEPENDS ON THE FREQUENCY OF AUTOREACTIVE T CELLS When the two different Tag-specific TCR-transgenic lines were crossed to the tolerant RT2 line, we found that only RT2/TCR1 mice established tolerance to Tag, as evident by deletion of most of the transgenic T cells and functional inactivation of the remaining ones. In contrast, RT2/TCR2 double-transgenic mice failed to develop peripheral T-cell tolerance. This result could be attributed to the different frequencies of autoreactive T cells in TCR1 versus TCR2 mice rather than intrinsic differences between the two lines, as demonstrated by two independent experimental approaches. In the first series of experiments, the frequency of Tag-specific T cells in TCR2 mice was reduced by generation of mixed bone-marrow chimaeras in which bone marrow derived from TCR2 mice was mixed at various ratios with bone marrow from nontransgenic mice and transferred into sublethally irradiated RT2 or negative control mice. Analyzing the tolerance status of these chimaeras, we could demonstrate that transgenic (Id+) T cells derived from TCR2 mice were susceptible to tolerance induction when present at low frequencies (i.e., less than 15% of peripheral CD4 T cells) ( F6rster et al., 1995 ). Conversely, in a different set of experiments, the frequency of Id T cells in TCR1 mice was increased to 100% by breeding of the TCR1 line into the RAG-l-deficient background (Mombaerts et al., 1992) . Interestingly, even in the absence of endogenous TCR rearrangements, the absolute number of transgenic T cells in TCR1/RAG-1 -/- mice remained low, that is, the (...truncated)


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Irmgard FöRster. Controlling Autoreactivity of CD4 T Cells by Local Tolerance Induction, Journal of Immunology Research, 6, DOI: 10.1155/1998/83953