Cerebral ischemia not only causes local CNS inflammation but also induces a generalized immunodepressive state mediated by an overactivation of the autonomic nervous system. Besides dysphagia, stroke-induced immunodepression (SIDS) is a key mechanism of stroke-associated pneumonia (SAP), which itself worsens stroke long-term outcome. Autoreactive CNS-antigen specific T cell responses are considered to be involved in secondary damage of ischemic brain damage. Whereas SAP boosts autoreactive immune responses after cerebral ischemia, SIDS ameliorates at least in part these responses. Recently, we demonstrated that antibody-mediated depletion of peripheral CD4+ T cells starting at day 3 after experimental stroke also prevents the infiltration of B cells (and to lesser extent of macrophages) into the ischemic CNS. This is associated with an antiproliferative effect on microglia/macrophages after experimental stroke. Between 7 and 14 days after brain ischemia, B-cells cluster together with CD4+ T cells within lymphoid follicle-like structures located centrally in the ischemic brain tissue. In these tertiary lymphoid organs, B cells differentiate into plasma cells producing antibodies recognizing CNS antigens. These findings are associated with a delayed cognitive deficit in experimental stroke. The observation that the cognitive decline can be prevented by peripheral CD20 depletion argues against a beneficial role of these naturally occurring antibodies.Here we hypothesize that activated microglia and monocytes/macrophages recruited from the periphery are essentially involved in the induction of humoral immune responses against CNS antigens after stroke by playing a key role in providing important cues for the recruitment, activation and differentiation of T and B cells and the development of post-ischemic tertiary lymphoid organs in the ischemic brain. In a mouse model of stroke (Middle Cerebral Artery occlusion; MCAo) we will investigate the functional roles of resident and blood-borne myeloid cells for the development of CNS antigen-specific autoimmune responses and delayed neurological deficits by depleting microglia and peripheral myeloid cells using transgenic mouse models (e.g. CX3Cr1CreERiDTR) as well as pharmacological tools (e.g. PLX3397). In addition, we will perform an in-depth characterisation of lymphoid follicle-like structures in the ischemic brain with a focus on the dynamics and requirements of soluble factors and cell-cell interaction between microglia/macrophages and lymphocytes. We will specifically deplete CXCL13 (B cell-attracting chemokine 1) in monocytes/macrophages. A better understanding of the interaction between innate and adaptive immune cells in the ischemic brain might contribute to the discovery of a causal treatment of the commonly observed post-stroke dementia and cognitive decline.