Toward a General Model of CD4 T cell Subset Specification and Memory Cell Formation

Overview

Journal Immunity

Publisher Cell Press

Specialty Allergy & Immunology

Date 2023 Mar 15

PMID 36921574

Authors

Kevin C Osum

Marc K Jenkins

Affiliations

Soon will be listed here.

Abstract

In the past few decades, a number of transformative discoveries have been made regarding memory CD8 T cell biology; meanwhile, the CD4 T cell field has lagged behind this progress. This perspective focuses on CD4 helper T (Th) cell subset specification and memory cell formation. Here, we argue that the sheer number of Th effector and memory cell subsets and a focus on their differences have been a barrier to a general model of CD4 memory T cell formation that applies to all immune responses. We highlight a bifurcation model that relies on an IL-2 signal-dependent switch as an explanation for the balanced production of diverse Th memory cells that participate in cell-mediated or humoral immunity in most contexts.

Citing Articles

CD301b dendritic cell-derived IL-2 dictates CD4 T helper cell differentiation.

Tatsumi N, El-Fenej J, Davila-Pagan A, Kumamoto Y Nat Commun. 2025; 16(1):2002.

PMID: 40011469 PMC: 11865452. DOI: 10.1038/s41467-025-55916-9.

Tissue-Resident Th2 Cells in Type 2 Immunity and Allergic Diseases.

Mannion J, Rahimi R Immunol Rev. 2025; 330(1):e70006.

PMID: 39981858 PMC: 11897987. DOI: 10.1111/imr.70006.

T and Treg Regulatory T Cell Subsets as Potential Indicators of Graft Tolerance Control in Kidney Transplant Recipients.

Rubino V, Carriero F, Palatucci A, Giovazzino A, Salemi F, Carrano R Int J Mol Sci. 2024; 25(19).

PMID: 39408939 PMC: 11477056. DOI: 10.3390/ijms251910610.

The contributions of T cell-mediated immunity to protection from vaccine-preventable diseases: A primer.

Shapiro J, Corrado M, Perry J, Watts T, Bolotin S Hum Vaccin Immunother. 2024; 20(1):2395679.

PMID: 39205626 PMC: 11364080. DOI: 10.1080/21645515.2024.2395679.

A review of CD4 T cell differentiation and diversity in dogs.

Lang H, Osum K, Friedenberg S Vet Immunol Immunopathol. 2024; 275:110816.

PMID: 39173398 PMC: 11421293. DOI: 10.1016/j.vetimm.2024.110816.

References

Riedel S . Edward Jenner and the history of smallpox and vaccination. Proc (Bayl Univ Med Cent). 2005; 18(1):21-5. PMC: 1200696. DOI: 10.1080/08998280.2005.11928028. View

Burton D, Ahmed R, Barouch D, Butera S, Crotty S, Godzik A . A Blueprint for HIV Vaccine Discovery. Cell Host Microbe. 2012; 12(4):396-407. PMC: 3513329. DOI: 10.1016/j.chom.2012.09.008. View

Ciucci T, Vacchio M, Gao Y, Tomassoni Ardori F, Candia J, Mehta M . The Emergence and Functional Fitness of Memory CD4 T Cells Require the Transcription Factor Thpok. Immunity. 2019; 50(1):91-105.e4. PMC: 6503975. DOI: 10.1016/j.immuni.2018.12.019. View

Tubo N, Pagan A, Taylor J, Nelson R, Linehan J, Ertelt J . Single naive CD4+ T cells from a diverse repertoire produce different effector cell types during infection. Cell. 2013; 153(4):785-96. PMC: 3766899. DOI: 10.1016/j.cell.2013.04.007. View

Krishnamoorthy V, Kannanganat S, Maienschein-Cline M, Cook S, Chen J, Bahroos N . The IRF4 Gene Regulatory Module Functions as a Read-Write Integrator to Dynamically Coordinate T Helper Cell Fate. Immunity. 2017; 47(3):481-497.e7. PMC: 5661949. DOI: 10.1016/j.immuni.2017.09.001. View

Morita R, Schmitt N, Bentebibel S, Ranganathan R, Bourdery L, Zurawski G . Human blood CXCR5(+)CD4(+) T cells are counterparts of T follicular cells and contain specific subsets that differentially support antibody secretion. Immunity. 2011; 34(1):108-21. PMC: 3046815. DOI: 10.1016/j.immuni.2010.12.012. View

Ahmed R, Gray D . Immunological memory and protective immunity: understanding their relation. Science. 1996; 272(5258):54-60. DOI: 10.1126/science.272.5258.54. View

Leon B, Bradley J, Lund F, Randall T, Ballesteros-Tato A . FoxP3+ regulatory T cells promote influenza-specific Tfh responses by controlling IL-2 availability. Nat Commun. 2014; 5:3495. PMC: 4013682. DOI: 10.1038/ncomms4495. View

Mackay C . Follicular homing T helper (Th) cells and the Th1/Th2 paradigm. J Exp Med. 2000; 192(11):F31-4. PMC: 2193096. DOI: 10.1084/jem.192.11.f31. View

10.

Altman J, Moss P, Goulder P, Barouch D, McHeyzer-Williams M, Bell J . Phenotypic analysis of antigen-specific T lymphocytes. Science. 1996; 274(5284):94-6. DOI: 10.1126/science.274.5284.94. View

11.

Homann D, Teyton L, Oldstone M . Differential regulation of antiviral T-cell immunity results in stable CD8+ but declining CD4+ T-cell memory. Nat Med. 2001; 7(8):913-9. DOI: 10.1038/90950. View

12.

Sabatino Jr J, Huang J, Zhu C, Evavold B . High prevalence of low affinity peptide-MHC II tetramer-negative effectors during polyclonal CD4+ T cell responses. J Exp Med. 2011; 208(1):81-90. PMC: 3023139. DOI: 10.1084/jem.20101574. View

13.

Choi J, Diao H, Faliti C, Truong J, Rossi M, Belanger S . Bcl-6 is the nexus transcription factor of T follicular helper cells via repressor-of-repressor circuits. Nat Immunol. 2020; 21(7):777-789. PMC: 7449381. DOI: 10.1038/s41590-020-0706-5. View

14.

Tuzlak S, Dejean A, Iannacone M, Quintana F, Waisman A, Ginhoux F . Repositioning T cell polarization from single cytokines to complex help. Nat Immunol. 2021; 22(10):1210-1217. DOI: 10.1038/s41590-021-01009-w. View

15.

Wu T, Shin H, Moseman E, Ji Y, Huang B, Harly C . TCF1 Is Required for the T Follicular Helper Cell Response to Viral Infection. Cell Rep. 2015; 12(12):2099-110. PMC: 4591235. DOI: 10.1016/j.celrep.2015.08.049. View

16.

Freeborn R, Strubbe S, Roncarolo M . Type 1 regulatory T cell-mediated tolerance in health and disease. Front Immunol. 2022; 13:1032575. PMC: 9650496. DOI: 10.3389/fimmu.2022.1032575. View

17.

Moon J, Chu H, Pepper M, McSorley S, Jameson S, Kedl R . Naive CD4(+) T cell frequency varies for different epitopes and predicts repertoire diversity and response magnitude. Immunity. 2007; 27(2):203-13. PMC: 2200089. DOI: 10.1016/j.immuni.2007.07.007. View

18.

Kotov J, Kotov D, Linehan J, Bardwell V, Gearhart M, Jenkins M . BCL6 corepressor contributes to Th17 cell formation by inhibiting Th17 fate suppressors. J Exp Med. 2019; 216(6):1450-1464. PMC: 6547868. DOI: 10.1084/jem.20182376. View

19.

Nurieva R, Chung Y, Martinez G, Yang X, Tanaka S, Matskevitch T . Bcl6 mediates the development of T follicular helper cells. Science. 2009; 325(5943):1001-5. PMC: 2857334. DOI: 10.1126/science.1176676. View

20.

Kunzli M, Reuther P, Pinschewer D, King C . Opposing effects of T cell receptor signal strength on CD4 T cells responding to acute versus chronic viral infection. Elife. 2021; 10. PMC: 7943189. DOI: 10.7554/eLife.61869. View