Cutting Edge: Tissue-retentive Lung Memory CD4 T Cells Mediate Optimal Protection to Respiratory Virus Infection

Overview

Journal J Immunol

Specialty Allergy & Immunology

Date 2011 Nov 8

PMID 22058417

Citations 398

Authors

John R Teijaro

Damian Turner

Quynh Pham

E John Wherry

Leo Lefrancois

Donna L Farber

Affiliations

Soon will be listed here.

Abstract

We identify in this article a new class of lung tissue-resident memory CD4 T cells that exhibit tissue tropism and retention independent of Ag or inflammation. Tissue-resident memory CD4 T cells in the lung did not circulate or emigrate from the lung in parabiosis experiments, were protected from in vivo Ab labeling, and expressed elevated levels of CD69 and CD11a compared with those of circulating memory populations. Importantly, influenza-specific lung-resident memory CD4 T cells served as in situ protectors to respiratory viral challenge, mediating enhanced viral clearance and survival to lethal influenza infection. By contrast, memory CD4 T cells isolated from spleen recirculated among multiple tissues without retention and failed to mediate protection to influenza infection, despite their ability to expand and migrate to the lung. Our results reveal tissue compartmentalization as a major determining factor for immune-mediated protection in a key mucosal site, important for targeting local protective responses in vaccines and immunotherapies.

Citing Articles

A variational deep-learning approach to modeling memory T cell dynamics.

van Dorp C, Gray J, Paik D, Farber D, Yates A bioRxiv. 2025; .

PMID: 40060443 PMC: 11888226. DOI: 10.1101/2024.07.08.602409.

T1-T2 Interplay in the Complex Immune Landscape of Severe Asthma.

Gauthier M, Kale S, Ray A Immunol Rev. 2025; 330(1):e70011.

PMID: 39991821 PMC: 11849004. DOI: 10.1111/imr.70011.

Lung-resident lymphocytes and their roles in respiratory infections and chronic respiratory diseases.

Sen Chaudhuri A, Sun J Chin Med J Pulm Crit Care Med. 2025; 2(4):214-223.

PMID: 39834580 PMC: 11742555. DOI: 10.1016/j.pccm.2024.11.006.

Tissue-resident immune cells: from defining characteristics to roles in diseases.

Li J, Xiao C, Li C, He J Signal Transduct Target Ther. 2025; 10(1):12.

PMID: 39820040 PMC: 11755756. DOI: 10.1038/s41392-024-02050-5.

Mucosal immune response in biology, disease prevention and treatment.

Zhou X, Wu Y, Zhu Z, Lu C, Zhang C, Zeng L Signal Transduct Target Ther. 2025; 10(1):7.

PMID: 39774607 PMC: 11707400. DOI: 10.1038/s41392-024-02043-4.

References

Gebhardt T, Wakim L, Eidsmo L, Reading P, Heath W, Carbone F . Memory T cells in nonlymphoid tissue that provide enhanced local immunity during infection with herpes simplex virus. Nat Immunol. 2009; 10(5):524-30. DOI: 10.1038/ni.1718. View

Hogan R, Zhong W, Usherwood E, Cookenham T, Roberts A, Woodland D . Protection from respiratory virus infections can be mediated by antigen-specific CD4(+) T cells that persist in the lungs. J Exp Med. 2001; 193(8):981-6. PMC: 2193400. DOI: 10.1084/jem.193.8.981. View

Moulton V, Bushar N, Leeser D, Patke D, Farber D . Divergent generation of heterogeneous memory CD4 T cells. J Immunol. 2006; 177(2):869-76. DOI: 10.4049/jimmunol.177.2.869. 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

Roti M, Yang J, Berger D, Huston L, James E, Kwok W . Healthy human subjects have CD4+ T cells directed against H5N1 influenza virus. J Immunol. 2008; 180(3):1758-68. PMC: 3373268. DOI: 10.4049/jimmunol.180.3.1758. View

Clark R, Chong B, Mirchandani N, Brinster N, Yamanaka K, Dowgiert R . The vast majority of CLA+ T cells are resident in normal skin. J Immunol. 2006; 176(7):4431-9. DOI: 10.4049/jimmunol.176.7.4431. View

Masopust D, Vezys V, Wherry E, Barber D, Ahmed R . Cutting edge: gut microenvironment promotes differentiation of a unique memory CD8 T cell population. J Immunol. 2006; 176(4):2079-83. DOI: 10.4049/jimmunol.176.4.2079. View

Bingaman A, Patke D, Mane V, Ahmadzadeh M, Ndejembi M, Bartlett S . Novel phenotypes and migratory properties distinguish memory CD4 T cell subsets in lymphoid and lung tissue. Eur J Immunol. 2005; 35(11):3173-86. DOI: 10.1002/eji.200526004. View

de Bree G, Daniels H, Van Schilfgaarde M, Jansen H, Out T, van Lier R . Characterization of CD4+ memory T cell responses directed against common respiratory pathogens in peripheral blood and lung. J Infect Dis. 2007; 195(11):1718-25. DOI: 10.1086/517612. View

10.

Verhoeven D, Teijaro J, Farber D . Pulse-oximetry accurately predicts lung pathology and the immune response during influenza infection. Virology. 2009; 390(2):151-6. PMC: 2776688. DOI: 10.1016/j.virol.2009.05.004. View

11.

Zinkernagel R . On natural and artificial vaccinations. Annu Rev Immunol. 2002; 21:515-46. DOI: 10.1146/annurev.immunol.21.120601.141045. View

12.

Liu L, Zhong Q, Tian T, Dubin K, Athale S, Kupper T . Epidermal injury and infection during poxvirus immunization is crucial for the generation of highly protective T cell-mediated immunity. Nat Med. 2010; 16(2):224-7. PMC: 3070948. DOI: 10.1038/nm.2078. View

13.

Piet B, de Bree G, Smids-Dierdorp B, van der Loos C, Remmerswaal E, von der Thusen J . CD8⁺ T cells with an intraepithelial phenotype upregulate cytotoxic function upon influenza infection in human lung. J Clin Invest. 2011; 121(6):2254-63. PMC: 3104744. DOI: 10.1172/JCI44675. View

14.

Teijaro J, Njau M, Verhoeven D, Chandran S, Nadler S, Hasday J . Costimulation modulation uncouples protection from immunopathology in memory T cell responses to influenza virus. J Immunol. 2009; 182(11):6834-43. DOI: 10.4049/jimmunol.0803860. View

15.

Masopust D, Vezys V, Usherwood E, Cauley L, Olson S, Marzo A . Activated primary and memory CD8 T cells migrate to nonlymphoid tissues regardless of site of activation or tissue of origin. J Immunol. 2004; 172(8):4875-82. DOI: 10.4049/jimmunol.172.8.4875. View

16.

Ndejembi M, Teijaro J, Patke D, Bingaman A, Chandok M, Azimzadeh A . Control of memory CD4 T cell recall by the CD28/B7 costimulatory pathway. J Immunol. 2006; 177(11):7698-706. DOI: 10.4049/jimmunol.177.11.7698. View

17.

Kirberg J, Baron A, Jakob S, Rolink A, Karjalainen K, von Boehmer H . Thymic selection of CD8+ single positive cells with a class II major histocompatibility complex-restricted receptor. J Exp Med. 1994; 180(1):25-34. PMC: 2191558. DOI: 10.1084/jem.180.1.25. View

18.

Teijaro J, Verhoeven D, Page C, Turner D, Farber D . Memory CD4 T cells direct protective responses to influenza virus in the lungs through helper-independent mechanisms. J Virol. 2010; 84(18):9217-26. PMC: 2937635. DOI: 10.1128/JVI.01069-10. View

19.

Marshall D, Turner S, Belz G, Wingo S, Andreansky S, Sangster M . Measuring the diaspora for virus-specific CD8+ T cells. Proc Natl Acad Sci U S A. 2001; 98(11):6313-8. PMC: 33465. DOI: 10.1073/pnas.101132698. View

20.

Cose S, Brammer C, Khanna K, Masopust D, Lefrancois L . Evidence that a significant number of naive T cells enter non-lymphoid organs as part of a normal migratory pathway. Eur J Immunol. 2006; 36(6):1423-33. DOI: 10.1002/eji.200535539. View