Histamine H₂ receptor signaling × environment interactions determine susceptibility to experimental allergic encephalomyelitis

Histamine and its receptors are important in both multiple sclerosis and experimental allergic encephalomyelitis (EAE). C57BL/6J (B6) mice deficient for the histamine H₂ receptor (H₂RKO) are less susceptible to EAE and exhibit blunted Th1 responses. However, whether decreased antigen-specific T-cell effector responses in H₂RKO mice were due to a lack of H₂R signaling in CD4⁺ T cells or antigen-presenting cells has remained unclear. We generated transgenic mice expressing H₂R specifically in T cells on the H₂RKO background, and, using wild-type B6 and H₂RKO mice as controls, induced EAE either in the presence or absence of the ancillary adjuvant pertussis toxin (PTX), which models the effects of infectious inflammatory stimuli on autoimmune disease. We monitored the mice for clinical signs of EAE and neuropathology, as well as effector T-cell responses using flow cytometry. EAE severity and neuropathology in H₂RKO mice expressing H ₂R exclusively in T cells become equal to those in wild-type B6 mice only when PTX is used to elicit disease. EAE complementation was associated with frequencies of CD4⁺IFN-γ⁺ and CD4⁺IL- 17⁺ cells that are equal to or greater than those in wild-type B6, respectively. Thus, the regulation of encephalitogenic T-cell responses and EAE susceptibility by H₂R signaling in CD4⁺ T cells is dependent on gene × environment interactions.