Infiltration of myelin‐specific T cells into the central nervous system induces the expression of proinflammatory cytokines in patients with multiple sclerosis (MS). We have previously shown that myelin‐specific T cells are recruited into zones of axonal degeneration, where they stimulate lesion‐reactive microglia. To gain mechanistic insight, we used RNA microarray analysis to compare the transcript profile in hippocampi from perforant pathway axonal‐lesioned mice with and without adoptively transferred myelin‐specific T cells 2 days postlesion, when microglia are clearly lesion reactive. Pathway analysis revealed that, among the 1,447 differently expressed transcripts, the interleukin (IL)‐1 pathway including all IL‐1 receptor ligands was upregulated in the presence of myelin‐specific T cells. Quantitative polymerase chain reaction showed increased mRNA levels of IL‐1β, IL‐1α, and IL‐1 receptor antagonist in the T‐cell–infiltrated hippocampi from axonal‐lesioned mice. In situ hybridization and immunohistochemistry showed a T‐cell–enhanced lesion‐specific expression of IL‐1β mRNA and protein, respectively, and induction of the apoptosis‐associated speck‐like protein, ASC, in CD11b+ cells. Double in situ hybridization showed colocalization of IL‐1β mRNA in a subset of CD11b mRNA+ cells, of which many were part of cellular doublets or clusters, characteristic of proliferating, lesion‐reactive microglia. Double‐immunofluorescence showed a T‐cell–enhanced colocalization of IL‐1β to CD11b+ cells, including lesion‐reactive CD11b+ ramified microglia. These results suggest that myelin‐specific T cells stimulate lesion‐reactive microglial‐like cells to produce IL‐1β. These findings are relevant to understand the consequences of T‐cell infiltration in white and gray matter lesions in patients with MS. GLIA 2016;64:407–424