Upon cerebral ischemia, an inflammatory reaction mediated by infiltrating immune cell subsets as well as activation of resident microglia cells has been shown to have both beneficial and detrimental effects on stroke outcome. We have found that in the chronic phase of stroke, B cells start to cluster with CD4+ T cells and myeloid cells and differentiate into plasma cells within ectopic lymphoid structures (ELS) in the ischemic brain. The observation that post-stroke cognitive decline was associated with the occurrence of brain-infiltrating B cells and CNS antigen-specific antibodies in stroke patients and could be prevented by B cell depletion in a mouse model of stroke, strongly suggests a pathophysiological role of CNS-directed humoral immune responses after stroke. Here, we hypothesize that activated microglia and infiltrating monocytes/macrophages together with infiltrating lymphocytes are essential for the induction and differentiation of lymphoid tissue-like PDGFRβ+ stromal cells, which in turn provide important cues for the recruitment, activation and differentiation of B cells within ELS in the ischemic brain. A better understanding of the crosstalk between myeloid cells, lymphocytes and stromal cells in establishing and maintaining ectopic lymphoid structures in the ischemic brain might contribute to the discovery of a causal treatment of poststroke cognitive decline.