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

Abstract

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 nonlymphoid 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.2 MainSeasonal influenza epidemics are a major cause of global morbidity and mortality. Although annually administered influenza vaccines are among the most widely used in the world, vaccine-elicited neutralizing antibodies offer poor protection against new influenza strains 1 . In contrast, there is evidence that prior influenza infection can accelerate viral clearance after heterotypic infection in both mice and humans 2,3,4,5,6 . Emerging data suggests that the targeted generation of CD4 memory T cells recognizing conserved epitopes from internal viral proteins may form the basis of a universal influenza virus vaccine 7,8 . CD4 memory T cells are induced following immunization or infection and can be recalled to generate secondary effectors during a challenge infection. Several subsets of CD4 memory cells have been described, including central memory (TCM) and effector memory (TEM) cells which circulate through secondary lymphoid and non-lymphoid tissues 9 . More recently, tissue resident memory (TRM) cells that persist in barrier tissues such as lung and skin have been described 10 . Although CD4 T cells actually outnumber CD8 T cells in barrier tissues, the majority of studies have focused on the requirements for CD8 TRM cell differentiation. In addition, although CD4 T cells are renowned for their substantial plasticity during immune responses, less is known about diversification within the CD4 TRM cell compartment 11,12,13,14,15,16 .Influenza i...

Transcriptomic and clonal characterization of T cells in the human central nervous system

“…We find that overall in CD4 CSF clusters, CD4 memory CSF.3 has the highest expression of genes related to all three signatures, followed by CD4 memory CSF.2, which had higher expression of all three signatures compared with CD4 clusters in the blood and CD4 memory CSF.1. This supports that, compared with the peripheral blood, the healthy CSF is enriched for CD4 T cells with T H 1 function, including a CD4 subtype with cytotoxic capacity, and that these cells may adapt to the tissue environment in ways similar to what has been described in other tissues (24,25,34).…”

“…The CD4 memory CSF.1 cluster was marked by expression of the subunits of the alpha 4 (ITGA4) beta 1 (ITGB1) integrin, which has been shown to be important for T cell entry into the CNS (1), KLRB1, and S1PR1 that promotes T cell egress from tissues (31). The other two CD4 clusters in the CSF (CD4 memory CSF.2 and CD4 memory CSF.3) have phenotypes similar to each other characterized by the chemokine receptor CXCR3 associated with T H 1 cells and CSF T cell trafficking (2,32) and markers that have been found in tissue-resident T cells and T cells residing within nonlymphoid tissues, including CCL5 (24,33,34), LGALS1 (24,25,34), PTGER2 (35), and CD69 (36). However, CD4 memory CSF.3 was also defined by the cytotoxicity-related genes GZMA, GZMK, GZMM, and CST7 (37), whereas CD4 memory CSF.2 was not.…”

Lung-resident memory B cells protect against bacterial pneumonia

“…This differs from influenza, which elicits these features in addition to lung BRM cells (8,11). The tendency to be associated with areas of iBALT varies among the distinct populations of lung TRM cells in influenza-recovered mouse lungs (40). However, B cell studies in the context of influenza have not reported lung B cells outside of iBALT (40)(41)(42), and it is therefore unclear whether influenza-generated lung BRM cells reside only in these structures.…”

“…The tendency to be associated with areas of iBALT varies among the distinct populations of lung TRM cells in influenza-recovered mouse lungs (40). However, B cell studies in the context of influenza have not reported lung B cells outside of iBALT (40)(41)(42), and it is therefore unclear whether influenza-generated lung BRM cells reside only in these structures. The current pneumococcus studies dissociate BRM cells from localization exclusively in iBALT and reveal that lung BRM cells can be components of histologically unremarkable lungs.…”

Tissue-Resident T Cells in Chronic Relapsing–Remitting Intestinal Disorders

“…Hence, also the responsiveness of T cells to chemokines in barrier tissues (and the mode of their regulation) is critical for defining the retention of T RM cells in the tissue. Some members of the the regulator of G protein signaling (RGS) family, including RGS1, are consistently overexpressed in T RM cells from barrier tissues [65,[81][82][83], but also in tumorinfiltrating T cells [84,85]. These RGS family members enhance the GTPase activity of GTP-bound Gαi (also Gαq) and, thus, inhibit Gαi/αq-coupled receptor signaling [86,87].…”