Self-Tolerance: Multiple Strategies for Peripheral Unresponsiveness of T Cells

Abstract

We discuss in this paper various strategies taken by the immune system to achieve and maintain the self-tolerance. Using transgenic mice with TcR ß and ß chain genes from a CD4 dependent self class II-reactive TH2 cell clone, we demonstrated that T cells expressing self-reactive TcR are not deleted in the thymus but are positively selected and released into the peripheral lymphoid pool. Transgenic mice with a large number of autoreactive T cells did not show any signs of autoimmunity and survived normally in specific pathogen free (SPF) conditions. The cells were, however, found not to be anergic, and fully retained the self class II reactivity in vitro to produce interleukins. Various degrees of down regulation of CD2 and costimulatory and cell surface marker molecules were detected. Upon stimulation in vivo, the autoreactive cells responded to downregulate the surface TcR of their own and inhibited the up regulation of class II antigen on antigen-presenting cells (APC). These results indicate that autoreactive T cells are rendered tolerant by diverse mechanisms rather than by simple clonal deletion and anergy.

Induction of allergen-specific tolerance may be one of the future solutions for allergic disorders. Different forms of tolerance exist, while the most well defined one should be “self-tolerance”, where the immune system prohibits the self reactivity of lymphocytes by various means preventing self injuries. The major cell type responsible for the induction and maintenance of self-tolerance is known to be the T cell.

It has been recognized that T cells with self-reactivity are generally deleted in the thymus by negative selection [1]. However, the negative selection in the thymus is not always complete and self-reactive T cells are known to survive in peripheral lymphoid tissues [2–4]. It is believed that such cells are either anergic or being suppressed under in vivo condition [5–9].

In support of the existence of autoreactive T cells in the periphery is the occurrence of the autologous mixed lymphocyte reaction (MLR) where a high frequency of autoreactive T cells are detected [10, 11]. There is a large number of established autoreactive T cell clones which respond to autologous antigen-presenting cells (APC) in the absence of exogenous antigen [12–14]. In general, more than 10% of randomly established T cell clones have been found to be autoreactive in our laboratory [14]. The questions we asked were how had such autoreactive T cells escaped from negative selection in the thymus, and how could such cells avoid the autoreactivity in vivo. We also asked what role was endowed with such autoreactive T cells in the immune system, which exist so frequently.

We discuss in this presentation several strategies taken by the immune system to avoid the self-reactivity of T cells in t cell receptor (TcR) transgenic mice which, as a whole, contribute to the establishment and maintenance of self-tolerance.