(417b) A Model for How T Cell-Mediated Autoimmunity Can be Triggered By Persistent Viral Infections

It has long been known that certain persistent infections can trigger the onset of T cell-mediated autoimmune diseases, but the reasons underlying this phenomenon remain unclear. T cell development in the thymus contributes to creating a largely self-tolerant and pathogen-specific mature repertoire. Some autoreactive T cells survive thymic development and circulate in peripheral tissues, but they usually do not result in autoimmunity. Theoretical and experimental studies suggest that activation of autoreactive T cells does not necessarily lead to a full-blown autoimmune response because a threshold number of T cells need to be activated in response to antigen for T cells to proliferate and differentiate into effector cells. Activation of such a “quorum” of T cells is more likely for foreign antigens compared to self-antigens because of the bias against autoreactive T cells conferred during thymic development. We developed a model for thymic development and then challenged the resulting mature T cell repertoire with varying intensities of infection. Persistent or intense infections were modeled by presenting increasing numbers of foreign antigens. Our results describe key parameters and conditions that result in persistent infections triggering T cell-mediated autoimmunity. Specifically, we describe how T cell activation by multiple foreign antigens can result in weakly autoreactive T cells exceeding the quorum threshold and mounting a response to self-antigens. These results highlight the importance of collective effects for T cell-mediated immunity and its aberrant regulation. Implications of our findings for phenomena such as epitope spreading, as well as possible experimental tests, will also be discussed.