Interleukin-2-secreting T helper cells promote extra-follicular B cell maturation via intrinsic regulation of a B cell mTOR-AKT-Blimp-1 axis

Caterina E Faliti¹, Maria Mesina², Jinyong Choi³, Simon Bélanger⁴, Monique A Marshall⁵, Christopher M Tipton⁵, Sakeenah Hicks⁶, Prashanti Chappa⁷, Maria A Cardenas⁸, Mohamed Abdel-Hakeem⁸, Theresa C Thinnes⁹, Christopher Cottrell¹⁰, Christopher D Scharer⁶, William R Schief¹¹, David Nemazee⁹, Matthew C Woodruff⁵, John M Lindner¹², Ignacio Sanz⁵, Shane Crotty¹³

Affiliations

¹ Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology (LJI), La Jolla, CA 92037, USA; Department of Medicine, Division of Rheumatology, Lowance Center for Human Immunology, Emory University, Atlanta, GA, USA; Emory Autoimmunity Center of Excellence, Emory University, Atlanta, GA, USA.
² Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology (LJI), La Jolla, CA 92037, USA.
³ Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology (LJI), La Jolla, CA 92037, USA; Department of Microbiology, Department of Biomedicine & Health Sciences, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
⁴ Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology (LJI), La Jolla, CA 92037, USA; VIR Biotechnology, San Francisco, CA 94158, USA.
⁵ Department of Medicine, Division of Rheumatology, Lowance Center for Human Immunology, Emory University, Atlanta, GA, USA; Emory Autoimmunity Center of Excellence, Emory University, Atlanta, GA, USA.
⁶ Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA.
⁷ Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA.
⁸ Emory University School of Medicine, Atlanta, GA, USA.
⁹ Scripps Consortium for HIV/AIDS Vaccine Development (CHAVD), La Jolla, CA 92037, USA.
¹⁰ Scripps Consortium for HIV/AIDS Vaccine Development (CHAVD), La Jolla, CA 92037, USA; Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA; IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA.
¹¹ Scripps Consortium for HIV/AIDS Vaccine Development (CHAVD), La Jolla, CA 92037, USA; Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA; IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA; The Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02139, USA.
¹² BioMed X Institute, 69120 Heidelberg, Germany.
¹³ Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology (LJI), La Jolla, CA 92037, USA; Scripps Consortium for HIV/AIDS Vaccine Development (CHAVD), La Jolla, CA 92037, USA; Department of Medicine, Division of Infectious Diseases and Global Public Health, University of California, San Diego (UCSD), La Jolla, CA 92037, USA. Electronic address: shane@lji.org.

PMID: 39612915
PMCID: PMC11675998 (available on 2025-12-10)
DOI: 10.1016/j.immuni.2024.11.006

Interleukin-2-secreting T helper cells promote extra-follicular B cell maturation via intrinsic regulation of a B cell mTOR-AKT-Blimp-1 axis

Caterina E Faliti et al. Immunity. 2024.

. 2024 Dec 10;57(12):2772-2789.e8.

doi: 10.1016/j.immuni.2024.11.006. Epub 2024 Nov 28.

Authors

Affiliations

¹ Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology (LJI), La Jolla, CA 92037, USA; Department of Medicine, Division of Rheumatology, Lowance Center for Human Immunology, Emory University, Atlanta, GA, USA; Emory Autoimmunity Center of Excellence, Emory University, Atlanta, GA, USA.
² Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology (LJI), La Jolla, CA 92037, USA.
³ Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology (LJI), La Jolla, CA 92037, USA; Department of Microbiology, Department of Biomedicine & Health Sciences, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
⁴ Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology (LJI), La Jolla, CA 92037, USA; VIR Biotechnology, San Francisco, CA 94158, USA.
⁵ Department of Medicine, Division of Rheumatology, Lowance Center for Human Immunology, Emory University, Atlanta, GA, USA; Emory Autoimmunity Center of Excellence, Emory University, Atlanta, GA, USA.
⁶ Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA.
⁷ Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA.
⁸ Emory University School of Medicine, Atlanta, GA, USA.
⁹ Scripps Consortium for HIV/AIDS Vaccine Development (CHAVD), La Jolla, CA 92037, USA.
¹⁰ Scripps Consortium for HIV/AIDS Vaccine Development (CHAVD), La Jolla, CA 92037, USA; Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA; IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA.
¹¹ Scripps Consortium for HIV/AIDS Vaccine Development (CHAVD), La Jolla, CA 92037, USA; Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA; IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA; The Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02139, USA.
¹² BioMed X Institute, 69120 Heidelberg, Germany.
¹³ Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology (LJI), La Jolla, CA 92037, USA; Scripps Consortium for HIV/AIDS Vaccine Development (CHAVD), La Jolla, CA 92037, USA; Department of Medicine, Division of Infectious Diseases and Global Public Health, University of California, San Diego (UCSD), La Jolla, CA 92037, USA. Electronic address: shane@lji.org.

PMID: 39612915
PMCID: PMC11675998 (available on 2025-12-10)
DOI: 10.1016/j.immuni.2024.11.006

Abstract

During antigen-driven responses, B cells can differentiate at extra-follicular (EF) sites or initiate germinal centers (GCs) in processes that involve interactions with T cells. Here, we examined the roles of interleukin (IL)-2 secreted by T helper (Th) cells during cognate interactions with activated B cells. IL-2 boosted the expansion of EF plasma cells and the secretion of low-mutated immunoglobulin G (IgG). Conversely, genetically disrupting IL-2 expression by CD4⁺ T cells, or IL-2 receptor (CD25) expression by B cells, promoted B cell entry into the GC and high-affinity antibody secretion. Mechanistically, IL-2 induced early mTOR activity, expression of the transcriptional regulator IRF4, and metabolic changes in B cells required to form Blimp-1-expressing plasma cells. Thus, T cell help via IL-2 regulates an mTOR-AKT-Blimp-1 axis in activated B cells, providing insight into the mechanisms that determine EF versus GC fates and positioning IL-2 as an early switch controlling plasma cell versus GC B cell commitment.

Keywords: CD4 T cells; IL-2 cytokine; T follicular helper cells; Tfh cells; antibodies; mTOR; metabolism; plasma cells; vaccine.

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Conflict of interest statement

Declaration of interests S.C. has consulted for GSK, JP Morgan, Citi, Morgan Stanley, Avalia NZ, Nutcracker Therapeutics, University of California, California State Universities, United Airlines, Adagio, Sanofi, and Roche. W.R.S. is inventor on patent applications related to immunogens in this manuscript filed by Scripps and IAVI. W.R.S. is an employee of Moderna, Inc. S.B. is a current employee of VIR Biotechnology and may possess shares of VIR Biotechnology.

References

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Interleukin-2-secreting T helper cells promote extra-follicular B cell maturation via intrinsic regulation of a B cell mTOR-AKT-Blimp-1 axis

Affiliations

Interleukin-2-secreting T helper cells promote extra-follicular B cell maturation via intrinsic regulation of a B cell mTOR-AKT-Blimp-1 axis

Authors

Affiliations

Abstract

Conflict of interest statement

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Molecular Biology Databases

Research Materials

Miscellaneous