Original Antigenic Sin in CD4+ T Cells

ABSTRACT Original antigenic sin (OAS) describes the phenomenon in which prior exposure to an antigen weakens the adaptive antibody response to a subsequent heterologous infection. This phenomenon can diminish the effectiveness of immunity acquired through vaccination or previous infections. We demonstrate that OAS arises because CD4+ T cell proliferation and regulation signals are antigen‐nonspecific. Rapidly responding memory CD4+ T cells trigger regulatory T cell (Tregs) responses, which prematurely suppress the naïve CD4+ T cell response, leading to a similar OAS effect in CD4+ T cells. This mechanism is illustrated through a mathematical model incorporating naïve and memory CD4+ T cell proliferation, interleukin‐2 (IL‐2), and Tregs. The model, calibrated with experimental data, employs numerical simulations to analyse how CD4+ T cell responses vary with the degree of cross‐reactivity between memory CD4+ T cells and the antigen associated with the secondary infection. The findings indicate that the immune response is weakest at an intermediate level of cross‐reactivity, a key characteristic of OAS. This mechanism may also explain OAS in antibody responses.