Peripheral Foxp3 regulatory T cells (pT) maintain immune homeostasis by controlling potentially harmful effector T cell responses toward dietary and microbial antigens. Although the identity of the T cell receptor (TCR) can impose commitment and functional specialization of T cells, less is known about how TCR identity governs pT development from conventional CD4 T cells. To investigate the extent to which TCR identity dictates pT fate, we used somatic cell nuclear transfer to generate a transnuclear (TN) mouse carrying a monoclonal TCR from a pT (pT TN mice). We found that the pT TCR did not inevitably predispose T cells to become pT but instead allowed for differentiation of noninflammatory CD4CD8αα intraepithelial lymphocytes (CD4) in the small intestine. Only when we limited the number of T cell precursors that carried the TN pT TCR did we observe substantial pT development in the mesenteric lymph nodes and small intestine lamina propria of mixed bone marrow chimeras. Small clonal sizes and therefore decreased intraclonal competition were required for pT development. Despite bearing the same TCR, small intestine CD4 developed independently of precursor frequency. Both pT and CD4 development strictly depended on the resident microbiota. A single clonal CD4 T cell precursor can thus give rise to two functionally distinct and anatomically segregated T cell subsets in a microbiota-dependent manner. Therefore, plasticity of the CD4 T cell compartment depends not only on the microbiota but also on specialized environmental cues provided by different tissues.
T cells expressing anti-CD19 chimeric antigen receptors (CARs) demonstrate impressive efficacy in the treatment of systemic B cell malignancies, including B cell lymphoma. However, their effect on primary central nervous system lymphoma (PCNSL) is unknown. Additionally, the detailed cellular dynamics of CAR T cells during their antitumor reaction remain unclear, including their intratumoral infiltration depth, mobility, and persistence. Studying these processes in detail requires repeated intravital imaging of precisely defined tumor regions during weeks of tumor growth and regression. Here, we have combined a model of PCNSL with in vivo intracerebral 2-photon microscopy. Thereby, we were able to visualize intracranial PCNSL growth and therapeutic effects of CAR T cells longitudinally in the same animal over several weeks. Intravenous (i.v.) injection resulted in poor tumor infiltration of anti-CD19 CAR T cells and could not sufficiently control tumor growth. After intracerebral injection, however, anti-CD19 CAR T cells invaded deeply into the solid tumor, reduced tumor growth, and induced regression of PCNSL, which was associated with long-term survival. Intracerebral anti-CD19 CAR T cells entered the circulation and infiltrated distant, nondraining lymph nodes more efficiently than mock CAR T cells. After complete regression of tumors, anti-CD19 CAR T cells remained detectable intracranially and intravascularly for up to 159 d. Collectively, these results demonstrate the great potential of anti-CD19 CAR T cells for the treatment of PCNSL.
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