Novel expression of MHC class II on DRG neurons and its role in promoting antinociceptive CD4+ T cells in females during chemotherapy- induced peripheral neuropathy

This pilot research project supported through the COBRE award P20GM103643 focused on neuro-immune interactions in neuropathic pain, exploring an unexpected mechanism by which primary sensory neurons in the dorsal root ganglion (DRG) may express MHC class II molecules and directly engage CD4+ T cells. This work reorients conventional thinking about antigen presentation and immune modulation in the peripheral nervous system by asking whether neuronal MHC class II contributes to activation of antinociceptive CD4+ T cell responses that promote resolution of neuropathic pain.

The laboratory brings together expertise in neuroimmunology, multi-color flow cytometry, multi-analyte assays, phospho-profiling, 2D DiGE and 2D Western and established mouse behavioral models of pain such as Hargreaves, von Frey, and thermal choice assays. These technical skills enable rigorous investigation of both cellular phenotype and functional consequence: detecting and characterizing MHC class II expression on neurons, profiling interacting T cell populations, and testing behavioral outcomes in well-characterized preclinical models of neuropathic pain. The project fits within a broader laboratory emphasis on how T cells impact neuronal response properties and how sex-specific mechanisms influence pain biology.

Previous findings from this group and collaborators have revealed sex-dependent mitochondrial regulation of neuronal function—mechanisms occurring in males but not females—underscoring the importance of evaluating sex as a biological variable in mechanisms of pain and recovery. The pilot project’s central hypothesis posits that neuronal MHC class II expression in the DRG is sufficient to present antigen or provide costimulatory signals that directly activate CD4+ T cells, driving immune-mediated processes that resolve neuropathic pain. To test this hypothesis, the research will combine molecular and cellular assays to confirm MHC class II expression on neurons, immunophenotyping to identify and characterize CD4+ T cells engaged by neuronal antigen presentation, and behavioral assays to determine whether modulating this neuron-T cell axis alters pain outcomes.

The study’s integrative approach aims to link molecular evidence to functional, organism-level consequences. If neuronal MHC class II proves to be a mechanism for activating antinociceptive CD4+ T cells, this would reveal a novel target for therapeutic strategies that harness or mimic endogenous immune-mediated resolution pathways. The work also has the potential to inform sex-specific treatment approaches, given Goode’s prior observations of sex differences in neuronal mitochondrial signaling related to pain. As a Pilot Project Leader within the COBRE Center for Pain Research, the study aims to generate preliminary data and mechanistic insight that can catalyze larger-scale investigations into neuron-immune communication as a pathway to resolve chronic and neuropathic pain syndromes.