The HLA-DRB1*15:01 allele-the strongest genetic risk factor for multiple sclerosis in Caucasians-has been implicated in shaping pathogenic CD4<sup>+</sup> T-cell responses and broader neuroimmune vulnerability, yet how this allele modulates age- and sex-dependent neuroimmune processes within the central nervous system (CNS) remains poorly defined.<h4>Methods</h4>We investigated the impact of HLA-DRB1*15:01 expression using a humanized mouse model (HLA mice) and wild-type (WT) controls. The gene discussed is CD4; the disease is multiple sclerosis.