Biology subjects

Swarnalekha, N.

Publications and source records attributed to Swarnalekha, N..

3 recordsLinked to original sources

bioRxiv2025

HIF-1α+ CD4 T cells coordinate a tissue resident immune cell network in the lung

A deeper understanding of how tissue localized immune cells arise and function is critical for developing mucosal vaccines. Currently, there are no murine models that specifically target tissue T cells while leaving their lymphoid counterparts untouched. Here we leverage the observation that during influenza infection, HIF-1 regulatory activity is higher in the lung compared to lymph node CD4 T cells. Inducible deletion of Hif1a in CD4 T cells, at the onset of its activity in the lung, reduces the tissue resident T cell compartment with minimal impact on peripheral immunity. HIF-1-active CD4 T cells occupy the border of tertiary lymphoid structures, where they coordinate an IL-21-dependent network of spatially co-localized immune cells including macrophages, NK cells and IgA+ B cells. A similar HIF-1-dependent network is engaged in a lung adenocarcinoma model, highlighting a broader role for HIF-1+ CD4 T cells in integrating protective immunity during infection and cancer.

immunology↗

bioRxiv2020

Redefining CD4 T cell residency: Helper T cells orchestrate protective humoral immunity in the lung

Influenza is a severe and acute respiratory pathogen, and a significant cause for morbidity, particularly in young children and the elderly. Following influenza infection, clonally expanded T cells take up permanent residence in the lung where they are poised to rapidly respond to challenge infection. The non-circulating status of these tissue resident memory (TRM) cells makes them an attractive target for vaccination. While many studies have characterized CD8 TRM cells, less is known about the heterogeneity and protective capacity of CD4 TRM cells. Here we characterized the dynamics and transcriptional regulation of lung resident CD4 T cells to define a non-lymphoid signature that removes the bias created by the prevalence of Th1 helper cells during viral infection. We identified a novel population of long-lived T resident helper (TRH) cells that requires intrinsic Bcl6 expression for their differentiation. Although TRH cells also depend on B cells, they are generated independently of T follicular helper effector cells in the lymph node. In contrast to lung resident Th1 cells, TRH cells are tightly co-localized with B cells in inducible Bronchus Associated Lymphoid Tissue (iBALT). Deletion of Bcl6 in CD4 T cells prior to heterotypic challenge infection results in redistribution of CD4 T cells outside of iBALT areas and impaired local antibody production. These data highlight lung iBALT as a niche for the homeostasis and survival of TRH cells, and further suggest that vaccination strategies to selectively induce TRH cells can improve protective immunity in the tissue.

immunology↗

bioRxiv2019

Persistence and plasticity of T follicular memory cells

CD4 memory T cells play an important role in protective immunity and are a key target in vaccine development. Many studies have focused on T central memory (TCM) cells, while the existence and functional significance of T follicular helper (TFH) memory cells is controversial. Here we show that TFH memory cells are highly susceptible to NAD induced cell death (NICD) during isolation from tissues, leading to their under-representation in prior studies. NICD blockade reveals the persistence of abundant TFH memory cells, with high expression of hallmark TFH markers, that persist to at least 400 days after infection, by which time TCM cells are no longer found. Using single cell RNA-seq we demonstrate that TFH memory cells are transcriptionally distinct from TCM cells, maintain stemness and self-renewal gene expression, and, in contrast to TCM cells, are multipotent following recall. Surprisingly, TFH memory cells concurrently express a distinct glycolytic signature similar to trained immune cells, including elevated expression of mTOR, HIF-1 and cAMP regulated genes. Late disruption of glycolysis/ICOS signaling leads to TFH memory cell depletion concomitant with decreased splenic plasma cells and circulating antibody titers, demonstrating both unique homeostatic regulation of memory TFH and their sustained function during the memory phase of the immune response. These results highlight the metabolic heterogeneity underlying distinct memory T cell subsets and establish TFH memory cells as an attractive target for the induction of long-lived adaptive immunity.\n\nHIGHLIGHTSO_LICell death during isolation from the tissue prevents the full recovery of TFH memory cells\nC_LIO_LITFH memory cells are transcriptionally distinct from TCM cells and maintain a broader recall capacity\nC_LIO_LITFH memory cells are maintained in the absence of antigen but require ICOS signaling and glycolysis\nC_LIO_LITFH memory cells support late phase antibody production by splenic plasma cells\nC_LI

immunology↗