CD4 Resident Memory T Cells Dominate Immunosurveillance and Orchestrate Local Recall Responses

Overview

Journal J Exp Med

Specialties Allergy & Immunology
General Medicine

Date 2019 Mar 30

PMID 30923043

Citations 111

Authors

Lalit K Beura

Nancy J Fares-Frederickson

Elizabeth M Steinert

Milcah C Scott

Emily A Thompson

Kathryn A Fraser

Jason M Schenkel

Vaiva Vezys

David Masopust

Affiliations

Soon will be listed here.

Abstract

This study examines the extent to which memory CD4 T cells share immunosurveillance strategies with CD8 resident memory T cells (T). After acute viral infection, memory CD4 T cells predominantly used residence to survey nonlymphoid tissues, albeit not as stringently as observed for CD8 T cells. In contrast, memory CD4 T cells were more likely to be resident within lymphoid organs than CD8 T cells. Migration properties of memory-phenotype CD4 T cells in non-SPF parabionts were similar, generalizing these results to diverse infections and conditions. CD4 and CD8 T shared overlapping transcriptional signatures and location-specific features, such as granzyme B expression in the small intestine, revealing tissue-specific and migration property-specific, in addition to lineage-specific, differentiation programs. Functionally, mucosal CD4 T reactivation locally triggered both chemokine expression and broad immune cell activation. Thus, residence provides a dominant mechanism for regionalizing CD4 T cell immunity, and location enforces shared transcriptional, phenotypic, and functional properties with CD8 T cells.

Citing Articles

Single cell profiling of circulating autoreactive CD4 T cells from patients with autoimmune liver diseases suggests tissue imprinting.

Cardon A, Guinebretiere T, Dong C, Gil L, Ado S, Gavlovsky P Nat Commun. 2025; 16(1):1161.

PMID: 39880819 PMC: 11779892. DOI: 10.1038/s41467-025-56363-2.

Tissue-resident memory CD8 T cell diversity is spatiotemporally imprinted.

Reina-Campos M, Monell A, Ferry A, Luna V, Cheung K, Galletti G Nature. 2025; 639(8054):483-492.

PMID: 39843748 PMC: 11903307. DOI: 10.1038/s41586-024-08466-x.

Tissue-resident memory T cells in diseases and therapeutic strategies.

Xie D, Lu G, Mai G, Guo Q, Xu G MedComm (2020). 2025; 6(1):e70053.

PMID: 39802636 PMC: 11725047. DOI: 10.1002/mco2.70053.

Combined TLR2/TLR4 activation equip non-mucosal dendritic cells to prime Th1 cells with gut tropism.

Zuquete S, Ferreira M, Delgado I, Gazalle P, Andaluz S, Rosa M iScience. 2025; 27(12):111232.

PMID: 39759015 PMC: 11700634. DOI: 10.1016/j.isci.2024.111232.

Deep profiling deconstructs features associated with memory CD8 T cell tissue residence.

Scott M, Steier Z, Pierson M, Stolley J, OFlanagan S, Soerens A Immunity. 2024; 58(1):162-181.e10.

PMID: 39708817 PMC: 11852946. DOI: 10.1016/j.immuni.2024.11.007.

References

Wherry E, Blattman J, Murali-Krishna K, van der Most R, Ahmed R . Viral persistence alters CD8 T-cell immunodominance and tissue distribution and results in distinct stages of functional impairment. J Virol. 2003; 77(8):4911-27. PMC: 152117. DOI: 10.1128/jvi.77.8.4911-4927.2003. View

Seder R, Ahmed R . Similarities and differences in CD4+ and CD8+ effector and memory T cell generation. Nat Immunol. 2003; 4(9):835-42. DOI: 10.1038/ni969. View

Nascimbeni M, Shin E, Chiriboga L, Kleiner D, Rehermann B . Peripheral CD4(+)CD8(+) T cells are differentiated effector memory cells with antiviral functions. Blood. 2004; 104(2):478-86. DOI: 10.1182/blood-2003-12-4395. View

Subramanian A, Tamayo P, Mootha V, Mukherjee S, Ebert B, Gillette M . Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005; 102(43):15545-50. PMC: 1239896. DOI: 10.1073/pnas.0506580102. View

Galkina E, Thatte J, Dabak V, Williams M, Ley K, Braciale T . Preferential migration of effector CD8+ T cells into the interstitium of the normal lung. J Clin Invest. 2005; 115(12):3473-83. PMC: 1288831. DOI: 10.1172/JCI24482. View

Robinson M, Smyth G . Moderated statistical tests for assessing differences in tag abundance. Bioinformatics. 2007; 23(21):2881-7. DOI: 10.1093/bioinformatics/btm453. View

Surh C, Sprent J . Homeostasis of naive and memory T cells. Immunity. 2008; 29(6):848-62. DOI: 10.1016/j.immuni.2008.11.002. View

Fazilleau N, McHeyzer-Williams L, Rosen H, McHeyzer-Williams M . The function of follicular helper T cells is regulated by the strength of T cell antigen receptor binding. Nat Immunol. 2009; 10(4):375-84. PMC: 2712297. DOI: 10.1038/ni.1704. View

Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N . The Sequence Alignment/Map format and SAMtools. Bioinformatics. 2009; 25(16):2078-9. PMC: 2723002. DOI: 10.1093/bioinformatics/btp352. View

10.

Robinson M, McCarthy D, Smyth G . edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics. 2009; 26(1):139-40. PMC: 2796818. DOI: 10.1093/bioinformatics/btp616. View

11.

Chen H, Boutros P . VennDiagram: a package for the generation of highly-customizable Venn and Euler diagrams in R. BMC Bioinformatics. 2011; 12:35. PMC: 3041657. DOI: 10.1186/1471-2105-12-35. View

12.

Taylor J, Jenkins M . CD4+ memory T cell survival. Curr Opin Immunol. 2011; 23(3):319-23. DOI: 10.1016/j.coi.2011.03.010. View

13.

Gebhardt T, Whitney P, Zaid A, Mackay L, Brooks A, Heath W . Different patterns of peripheral migration by memory CD4+ and CD8+ T cells. Nature. 2011; 477(7363):216-9. DOI: 10.1038/nature10339. View

14.

Pepper M, Pagan A, Igyarto B, Taylor J, Jenkins M . Opposing signals from the Bcl6 transcription factor and the interleukin-2 receptor generate T helper 1 central and effector memory cells. Immunity. 2011; 35(4):583-95. PMC: 3208313. DOI: 10.1016/j.immuni.2011.09.009. View

15.

Teijaro J, Turner D, Pham Q, Wherry E, Lefrancois L, Farber D . Cutting edge: Tissue-retentive lung memory CD4 T cells mediate optimal protection to respiratory virus infection. J Immunol. 2011; 187(11):5510-4. PMC: 3221837. DOI: 10.4049/jimmunol.1102243. View

16.

Yu G, Wang L, Han Y, He Q . clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS. 2012; 16(5):284-7. PMC: 3339379. DOI: 10.1089/omi.2011.0118. View

17.

Bromley S, Yan S, Tomura M, Kanagawa O, Luster A . Recirculating memory T cells are a unique subset of CD4+ T cells with a distinct phenotype and migratory pattern. J Immunol. 2012; 190(3):970-6. PMC: 3618989. DOI: 10.4049/jimmunol.1202805. View

18.

Sathaliyawala T, Kubota M, Yudanin N, Turner D, Camp P, Thome J . Distribution and compartmentalization of human circulating and tissue-resident memory T cell subsets. Immunity. 2012; 38(1):187-97. PMC: 3557604. DOI: 10.1016/j.immuni.2012.09.020. View

19.

Schenkel J, Fraser K, Vezys V, Masopust D . Sensing and alarm function of resident memory CD8⁺ T cells. Nat Immunol. 2013; 14(5):509-13. PMC: 3631432. DOI: 10.1038/ni.2568. View

20.

Hale J, Youngblood B, Latner D, Mohammed A, Ye L, Akondy R . Distinct memory CD4+ T cells with commitment to T follicular helper- and T helper 1-cell lineages are generated after acute viral infection. Immunity. 2013; 38(4):805-17. PMC: 3741679. DOI: 10.1016/j.immuni.2013.02.020. View