Biology subjects

Kolz, A.

Publications and source records attributed to Kolz, A..

3 recordsLinked to original sources

bioRxiv2023

T:B cell communication in ectopic lymphoid follicles in CNS autoimmunity

Meningeal ectopic lymphoid follicle-like structures (eLFs) have been described in multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE), but their role in CNS autoimmunity is unclear. To analyze the cellular phenotypes and interactions within these structures, we employed a Th17 adoptive transfer EAE model featuring formation of large, numerous eLFs. Single-cell transcriptomic analysis revealed that clusters of activated B cells and B1/Marginal Zone-like B cells are overrepresented in the CNS and identified B cells poised for undergoing antigen-driven germinal center (GC) reactions and clonal expansion in the CNS. Furthermore, CNS B cells showed enhanced capacity for antigen presentation and immunological synapse formation compared to peripheral B cells. To directly visualize Th17:B cell cooperation in eLFs, we labeled Th17 cells with a ratiometric calcium sensor, and tracked their interactions with tdTomato-labeled B cells in real-time. Thereby, we demonstrated for the first time that T and B cells form long-lasting antigen-specific contacts in meningeal eLFs that result in reactivation of autoreactive T cells. Consistent with these findings, autoreactive T cells depended on CNS B cells to maintain a pro-inflammatory cytokine profile in the CNS. Collectively, our study reveals that extensive T:B cell cooperation occurs in meningeal eLFs in our model promoting differentiation and clonal expansion of B cells, as well as reactivation of CNS T cells and thereby supporting smoldering inflammatory processes within the CNS compartment. Our results provide valuable insights into the function of eLFs and may provide a direction for future research in MS.

immunology↗

bioRxiv2023

Memory Th1 cells modulate heterologous diseases through innate function

Through immune memory, infections have a lasting effect on the host. While memory cells enable accelerated and enhanced responses upon re-challenge with the same pathogen, their impact on susceptibility to unrelated diseases is unclear. We identify a subset of memory T helper 1 (Th1) cells termed innate acting memory T (TIA) cells that originate from a viral infection and produce IFN-{gamma} with innate kinetics upon heterologous challenge in vivo. Activation of memory TIA cells is induced in response to IL-12 in combination with IL-18 or IL-33 but is TCR-independent. Rapid IFN-{gamma} production by memory TIA cells is protective in subsequent heterologous challenge with the bacterial pathogen Legionella pneumophila. In contrast, antigen-independent re-activation of CD4+ memory TIA cells accelerates disease onset in an autoimmune model of multiple sclerosis. Our findings demonstrate that memory Th1 cells can acquire additional TCR-independent functionality to mount rapid, innate-like responses that modulate susceptibility to heterologous challenges.

immunology↗

bioRxiv2021

T cells modulate the microglial response to brain ischemia

Neuroinflammation after stroke is characterized by the activation of resident microglia and the invasion of circulating leukocytes into the brain. Although lymphocytes infiltrate the brain in small number, they have been consistently demonstrated to be the most potent leukocyte subpopulation contributing to secondary inflammatory brain injury. However, the exact mechanism how this minimal number of lymphocytes can profoundly affect stroke outcome is still largely elusive. Here, using a mouse model for ischemic stroke, we demonstrated that early activation of microglia in response to stroke is differentially regulated by distinct T cell subpopulations. Acute treatment with engineered T cells overexpressing IL-10 administered into the cisterna magna after stroke induces a switch of microglial gene expression to a profile associated with pro-regenerative functions. These findings substantiate the role of T cells in stroke with large impact on the cerebral inflammatory milieu by polarizing the microglial phenotype. Targeting T cell-microglia interactions can have direct translational relevance for further development of immune-targeted therapies for stroke and other neuroinflammatory conditions. SummaryThe crosstalk between brain infiltrating T cells and microglia in response to stroke remains elusive. Benakis et al. report that transcriptional signature of the stroke-associated microglia is reprogrammed by distinct T cell subpopulations. Engineered T cells overexpressing IL-10 administered four hours after stroke reinitiate microglial function inducing a pro-regenerative environment.

immunology↗