Biology subjects

Rangachari, M.

Publications and source records attributed to Rangachari, M..

5 recordsLinked to original sources

bioRxiv2025

Myelin antigen-specific effector CD8+ T cells induce chronic CNS autoimmunity in a CD4+ T cell-dependent manner.

Both CD4+ and CD8+ T cells play critical roles in the immunopathogenesis of multiple sclerosis (MS). 1C6 T cell receptor transgenic (TcR-Tg) mice on the nonobese diabetic (NOD) background have a MOG[35-55]-specific, MHC class II-restricted, TcR that selects for both CD4+ and CD8+ T cells. Adoptive transfer of 1C6 CD4+ T helper 17 (Th17) cells can induce experimental autoimmune encephalomyelitis (EAE) with a progressive disease course. In the current study, we assessed the function and pathogenicity of 1C6 CD8+ T cells. We found that they proliferated and produced inflammatory cytokines in response to MOG[35-55] peptide under both T cytotoxic 1 (Tc1) and Tc17 differentiation conditions, albeit with reduced expansion relative to their Th1 or Th17 counterparts. Both 1C6 Tc1 and Tc17 cells were able to induce EAE upon adoptive transfer to NOD.Scid mice. Intriguingly, we noted in vivo expansion of CD4+ T cells in the spleen and CNS of NOD.Scid recipients as well as in lymphocyte-sufficient animals, despite 1C6 Tc cells being purified on CD8 expression prior to transfer. Furthermore, 1C6 Tc17 cells expressed ThPOK, a master differentiation factor for CD4+ T cells. Finally, anti-CD4+ T cell blockade abrogated CD8+ T cell infiltration of the CNS and disease induction in Tc17 recipient mice. Our data provide insight into the interplay of CD4+ and CD8+ T cells in CNS autoimmunity.

immunology↗

bioRxiv2023

Serpine1 negatively regulates Th1 cell responses in experimental autoimmune encephalomyelitis.

Th1 cells are critical in experimental autoimmune encephalomyelitis (EAE). Serpine1 has been posited as an inhibitor of IFN{gamma} from T cells though its role in autoimmunity remains unclear. Here, we show that Serpine1 knockout (KO) mice develop EAE of enhanced severity relative to wild-type (WT) controls. Serpine1 overexpression represses Th1 cell cytokine production and pathogenicity, while Serpine1-KO:2D2 Th1 cells transfer EAE of increased severity in comparison to WT 2D2 Th1 cells. Notably, polarized Serpine1-KO Th1 cells display delayed expression of the Th1-specific inhibitory receptor, Tim-3. Serpine1-KO:Tim-3-Tg Th1 cells, which transgenically over-express Tim-3, showed increased expression of IFN{gamma} and reduced expression of the checkpoint molecules Lag-3 and PD-1 relative to WT Tim-3-Tg counterparts. Further, Serpine1 deficiency restored the EAE phenotype of Tim-3-Tg mice that normally develop mild disease. Together, we identify Serpine1 as a negative regulator of Th1 cells. Key pointsO_LISerpine1 inhibits EAE in a T cell-dependent manner. C_LIO_LISerpine1 is upregulated in Th1 cells and inhibits their pathogenicity. C_LIO_LISerpine1 promotes expression and function of Th1-specific inhibitory receptor Tim-3. C_LI

immunology↗

bioRxiv2022

Carcinogen induced expansion of atypical B cells and pre-treatment tumor adjacent tertiary lymphoid structures associate with poor response to BCG in non-muscle invasive bladder cancer

Poor response to Bacillus Calmette-Guerin (BCG) immunotherapy remains a major barrier in the management of patients with non-muscle-invasive bladder cancer (NMIBC). Among the multiple factors contributing to poor outcomes, a B cell infiltrated pre-treatment immune microenvironment of NMIBC tumors has emerged as a key determinant of response to BCG. The mechanisms underlying the paradoxical roles of B cells in NMIBC are poorly understood. Here, we show that B cell dominant tertiary lymphoid structures (TLSs), a hallmark feature of chronic mucosal immune response, are abundant and located close to the epithelial compartment in pre-treatment tumors from BCG non-responders. Digital spatial proteomic profiling of whole tumor sections revealed higher expression of immune exhaustion-associated proteins within the TLSs from both responders and non-responders. Chronic local inflammation, induced by the N-butyl- N-(4-hydroxybutyl) nitrosamine (BBN) carcinogen, led to TLS formation with recruitment and differentiation of the immunosuppressive atypical B cell (ABCs) subset within the bladder microenvironment, predominantly in aging female mice compared to their male counterparts. Depletion of ABCs simultaneous to BCG treatment delayed cancer progression in female mice. Our findings provide the first evidence indicating the role of ABCs in BCG response and will inform future development of therapies targeting the B cell exhaustion axis.

cancer biology↗

bioRxiv2019

MOG-reactive B cells exacerbate the severity of CD4+ T cell-driven CNS autoimmunity

Multiple sclerosis (MS) is an autoimmune disorder of the central nervous system (CNS) that has traditionally been considered a T cell-mediated disease. However, accumulating evidence points to a crucial role for B cells in disease processes. IgH[MOG] mice possess a transgenic immunoglobulin heavy chain derived from a monoclonal antibody specific to myelin oligodendrocyte glycoprotein (MOG), a key target for autoimmune responses. Here, using the experimental autoimmune encephalomyelitis (EAE) model of MS, we investigated the susceptibility of IgH[MOG] mice to CD4+ T cell-driven disease that was induced by active immunization with MOG[35-55] autoantigen. We found that immunized IgH[MOG] mice rapidly developed severe EAE, characterized by the aggregation of T and B cells in the CNS meninges. We observed an increased presence of class-switched and inflammatory cytokine-positive B cells in the IgH[MOG] CNS, as well as a greater frequency of IL-17- and GM-CSF-producing CD4+ T cells. Production of the Th17 maintenance factor IL-23 was increased from IgH[MOG] CNS-infiltrating B cells, and in vivo blockade of IL-23p19 strongly attenuated disease severity in IgH[MOG] mice. Strikingly, we observed an increased frequency of PD-1+CXCR5- T peripheral helper (Tph)-like cells in the CNS parenchyma and dura mater of IgH[MOG] mice. Both Tph accumulation in the CNS, as well as meningeal inflammation, were again sharply reduced upon IL-23p19 blockade in vivo. Notably, CNS-infiltrating B and Tph cells from IgH[MOG] mice showed an upregulation of genes related to neurodegeneration and oxidative phosphorylation, and IL-23 blockade reduced ROS production from these cells in vivo. Altogether, these data show that MOG-specific B cells contribute to severe CD4+ T cell-driven EAE by promoting CNS accumulation of Th17 and Tph cells, as well as tertiary lymphoid organs in the CNS meninges, in an IL-23 dependent manner.

immunology↗

bioRxiv2019

Male sex exacerbates the plasticity and pathogenicity of Th17 cells in a chronic model of CNS autoimmunity.

Sex differences in the incidence and severity of multiple sclerosis (MS) have long been recognized. However, the underlying cellular and molecular mechanisms for why male sex is associated with more aggressive and debilitating disease remain poorly defined. Using an T cell adoptive transfer model of chronic EAE, we find that male Th17 cells induced disease of increased severity relative to female Th17 cells, irrespective of whether transferred to male or female recipients. Throughout the disease course, a greater frequency of male Th17 cells produced the heterodox cytokine IFN{gamma}, a hallmark of pathogenic Th17 responses. Intriguingly, sex chromosomal complement, and not hormones, were responsible for the increased pathogenicity of male Th17 cells and an X-linked immune regulator, Jarid1c, was downregulated in both pathogenic male Th17 and CD4+ T cells from men with MS. Together, our data indicate that male sex critical regulates Th17 cell plasticity and pathogenicity via sex chromosomal complement.

immunology↗