CD4+ resident memory T cells dominate immunosurveillance and orchestrate local recall responses

Beura, Lalit K.; Fares-Frederickson, Nancy J; Steinert, Elizabeth M.; Scott, Milcah C.; Thompson, Emily A.; Fraser, Kathryn; Schenkel, Jason M.; Vezys, Vaiva; Masopust, David

doi:10.1084/jem.20181365

Cited by 157 publications

(186 citation statements)

References 62 publications

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“…1e, f) 22 . The presence of Th subset-specific genes in both NLT and LT cells reported here and elsewhere calls for a refinement of the residency signature that separates function from niche 11,12 .…”

mentioning

confidence: 53%

“…In support of this idea, TFH memory cells isolated from the spleen after LCMV infection were recently demonstrated to have a partially overlapping transcriptional signature with TRM cells, consistent with the non-circulating nature of both subsets 26 . In contrast, another study addressing the relationship between TRM cells present in secondary lymphoid organs and TFH memory cells reported more distinct transcriptional profiles of these subsets 12 . However, in this case the authors focused on gene expression in T cell receptor (TCR) transgenic cells that have relatively impaired TFH memory cell generation compared to polyclonal antigen specific cells 26 In this study we characterized the dynamics and diversification of polyclonal CD4 T cells present in the lung and draining LN after influenza, using the resolution provided by scRNAseq to decouple residency and functional signatures between these two compartments.…”

Section: Mainmentioning

confidence: 94%

Section: Mainmentioning

confidence: 99%

“…Importantly, CD4 T cell intrinsic deletion of Bcl6 at late time points after primary infection impairs the local humoral response upon reinfection. These data identify a novel TRH subset that may be a rational target to drive potent and protective immunity in the lung mucosa 11,12 .…”

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confidence: 92%

“…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 infection induces the differentiation of CD4 TRM cells in the lung, where they are maintained in an antigen and inflammation independent manner 17 . Following a lethal re-challenge, influenza specific CD4 TRM cells rapidly produce effector cytokines and promote both viral clearance and host survival 7 .…”

mentioning

confidence: 99%

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

Swarnalekha

Schreiner

Litzler

et al. 2020

Preprint

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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...

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mentioning

confidence: 53%

Section: Mainmentioning

confidence: 94%

Section: Mainmentioning

confidence: 99%

mentioning

confidence: 92%

mentioning

confidence: 99%

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

Swarnalekha

Schreiner

Litzler

et al. 2020

Preprint

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Synovial fluid CD69⁺CD8⁺ T cells with tissue‐resident phenotype mediate perforin‐dependent citrullination in rheumatoid arthritis

Jung

Lee

et al. 2020

Clin & Trans Imm

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ObjectivesAlthough the importance of tissue‐resident memory T (TRM) cells in organ‐specific chronic inflammation has been recognised, little is known about their role in rheumatoid arthritis (RA). Here, we examined the characteristics of synovial fluid CD8+ T cells that express canonical TRM markers CD69 and CD103, and their role in the pathogenesis of RA.MethodsSynovial fluid mononuclear cells (SFMCs) were obtained from patients with RA. Flow cytometric analysis of surface markers and cytotoxic molecules of CD8+ T cells was performed. TCR repertoire of CD8+ T cells was analysed by TCRVβ CDR3 sequencing. Citrullination with the formation of neutrophil extracellular trap (NET) was evaluated by immunofluorescence staining.ResultsThe frequency of CD8+ T cells was increased in SFMCs, and these CD8+ T cells were primarily comprised of CD45RA‐ memory T cells expressing CD69 and/or CD103. CD69+CD8+ T cells exhibited TRM phenotypes, including upregulation of CXCR6, CD49a and CD101, and downregulation of S1PR1 and KLF2. TCR repertoire analysis showed that these cells were an oligoclonally expanded population with increased expression of cytotoxic molecules. The treatment of neutrophils with supernatant from IL‐15‐stimulated CD69+CD8+ T cells induced perforin‐mediated histone citrullination and NET formation irrespective of their CD103 expression. The frequency of perforin‐expressing cells among CD69+CD8+ T cells in SFMCs was significantly higher in patients with anti‐citrullinated protein antibody (ACPA) than in those without ACPA.ConclusionCD69+CD8+ T cells in the SFMCs of RA patients exhibit TRM‐like features. These cells may participate in the pathogenesis of RA via perforin‐mediated citrullination.

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Guidelines for the use of flow cytometry and cell sorting in immunological studies (second edition)

et al. 2019

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These guidelines are a consensus work of a considerable number of members of the immunology and flow cytometry community. They provide the theory and key practical aspects of flow cytometry enabling immunologists to avoid the common errors that often undermine immunological data. Notably, there are comprehensive sections of all major immune cell types with helpful Tables detailing phenotypes in murine and human cells. The latest flow cytometry techniques and applications are also described, featuring examples of the data that can be generated and, importantly, how the data can be analysed. Furthermore, there are sections detailing tips, tricks and pitfalls to avoid, all written and peer‐reviewed by leading experts in the field, making this an essential research companion.

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CD4+ resident memory T cells dominate immunosurveillance and orchestrate local recall responses

Abstract: CD4 T cell localization impacts function and differentiation. Beura et al. show that memory CD4+ T cells are largely resident in both lymphoid and non-lymphoid tissues, organize local recall responses, and share overlapping transcriptional and location-specific features with CD8+ TRM.

Cited by 157 publications

References 62 publications

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

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

Synovial fluid CD69⁺CD8⁺ T cells with tissue‐resident phenotype mediate perforin‐dependent citrullination in rheumatoid arthritis

Guidelines for the use of flow cytometry and cell sorting in immunological studies (second edition)

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CD4+ resident memory T cells dominate immunosurveillance and orchestrate local recall responses

Abstract: CD4 T cell localization impacts function and differentiation. Beura et al. show that memory CD4+ T cells are largely resident in both lymphoid and non-lymphoid tissues, organize local recall responses, and share overlapping transcriptional and location-specific features with CD8+ TRM.

Cited by 157 publications

References 62 publications

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

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

Synovial fluid CD69+CD8+ T cells with tissue‐resident phenotype mediate perforin‐dependent citrullination in rheumatoid arthritis

Guidelines for the use of flow cytometry and cell sorting in immunological studies (second edition)

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Synovial fluid CD69⁺CD8⁺ T cells with tissue‐resident phenotype mediate perforin‐dependent citrullination in rheumatoid arthritis