Two distinct durable human class-switched memory B cell populations are induced by vaccination and infection

Cory A Perugino¹, Hang Liu², Jared Feldman², Jess Marbourg³, Thomas V Guy², Anson Hui², Nicole Ingram², Julian Liebaert², Neha Chaudhary³, Weiyang Tao³, Catherine Jacob-Dolan⁴, Blake M Hauser², Zayd Mian², Anusha Nathan², Zezhou Zhao², Clarety Kaseke², Rhoda Tano-Menka², Matthew A Getz², Fernando Senjobe², Cristhian Berrios⁵, Onosereme Ofoman⁵, Zachary Manickas-Hill², Duane R Wesemann⁶, Jacob E Lemieux⁷, Marcia B Goldberg⁸, Kerstin Nündel⁹, Ann Moormann⁹, Ann Marshak-Rothstein⁹, Regina C Larocque¹⁰, Edward T Ryan¹⁰, John A Iafrate¹¹, Daniel Lingwood², Gaurav Gaiha¹², Richelle Charles¹⁰, Alejandro B Balazs², Aridaman Pandit³, Vivek Naranbhai¹³, Aaaron G Schmidt¹⁴, Shiv Pillai¹⁵

Affiliations

¹ Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA; Division of Rheumatology Allergy and Immunology, Massachusetts General Hospital, Boston, MA 02114, USA.
² Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA.
³ Abbvie Cambridge Research Center, Cambridge, MA 02139, USA.
⁴ Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA; Monash University, Melbourne, VIC 3800, Australia.
⁵ Department of Pathology, Massachusetts Hospital, Boston, MA 02114, USA.
⁶ Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
⁷ Infectious Diseases Division, Massachusetts Hospital, Boston, MA 02114, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA.
⁸ Infectious Diseases Division, Massachusetts Hospital, Boston, MA 02114, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA; Department of Microbiology, Harvard Medical School, Boston, MA 02115, USA.
⁹ University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
¹⁰ Infectious Diseases Division, Massachusetts Hospital, Boston, MA 02114, USA.
¹¹ MGH Cancer Center, Massachusetts Hospital, Boston, MA 02114, USA.
¹² Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA; Gastrointestinal Unit, Massachusetts Hospital, Boston, MA 02114, USA.
¹³ MGH Cancer Center, Massachusetts Hospital, Boston, MA 02114, USA; Monash University, Melbourne, VIC 3800, Australia; Center for the AIDS Programme of Research in South Africa, Durban 4001, South Africa.
¹⁴ Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA; Department of Microbiology, Harvard Medical School, Boston, MA 02115, USA.
¹⁵ Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA. Electronic address: spillai@mgh.harvard.edu.

PMID: 40173042
DOI: 10.1016/j.celrep.2025.115472

Free article

Two distinct durable human class-switched memory B cell populations are induced by vaccination and infection

Cory A Perugino et al. Cell Rep. 2025.

Free article

. 2025 Apr 22;44(4):115472.

doi: 10.1016/j.celrep.2025.115472. Epub 2025 Apr 1.

Authors

Affiliations

¹ Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA; Division of Rheumatology Allergy and Immunology, Massachusetts General Hospital, Boston, MA 02114, USA.
² Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA.
³ Abbvie Cambridge Research Center, Cambridge, MA 02139, USA.
⁴ Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA; Monash University, Melbourne, VIC 3800, Australia.
⁵ Department of Pathology, Massachusetts Hospital, Boston, MA 02114, USA.
⁶ Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
⁷ Infectious Diseases Division, Massachusetts Hospital, Boston, MA 02114, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA.
⁸ Infectious Diseases Division, Massachusetts Hospital, Boston, MA 02114, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA; Department of Microbiology, Harvard Medical School, Boston, MA 02115, USA.
⁹ University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
¹⁰ Infectious Diseases Division, Massachusetts Hospital, Boston, MA 02114, USA.
¹¹ MGH Cancer Center, Massachusetts Hospital, Boston, MA 02114, USA.
¹² Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA; Gastrointestinal Unit, Massachusetts Hospital, Boston, MA 02114, USA.
¹³ MGH Cancer Center, Massachusetts Hospital, Boston, MA 02114, USA; Monash University, Melbourne, VIC 3800, Australia; Center for the AIDS Programme of Research in South Africa, Durban 4001, South Africa.
¹⁴ Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA; Department of Microbiology, Harvard Medical School, Boston, MA 02115, USA.
¹⁵ Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA. Electronic address: spillai@mgh.harvard.edu.

PMID: 40173042
DOI: 10.1016/j.celrep.2025.115472

Abstract

Memory lymphocytes are durable cells that persist in the absence of antigen, but few human B cell subsets have been characterized in terms of durability. The relative durability of eight non-overlapping human B cell sub-populations covering 100% of all human class-switched B cells was interrogated. Only two long-lived B cell populations persisted in the relative absence of antigen. In addition to canonical germinal center-derived switched-memory B cells with an IgD^-CD27⁺CXCR5⁺ phenotype, a second, non-canonical, but distinct memory population of IgD^-CD27^-CXCR5⁺ DN1 B cells was also durable, exhibited a unique TP63-linked transcriptional and anti-apoptotic signature, had low levels of somatic hypermutation, but was more clonally expanded than canonical switched-memory B cells. DN1 B cells likely evolved to preserve immunological breadth and may represent the human counterparts of rodent extrafollicular memory B cells that, unlike canonical memory B cells, can enter germinal centers and facilitate B cell and antibody evolution.

Keywords: CP: Immunology; TP63 in lymphocytes; clonal diversity; extrafollicular memory B cells; germinal center derived memory B cells; human B cells; human class-switched memory B cells; humoral immune durability; lymphocyte durability.

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Conflict of interest statement

Declaration of interests S.P. is on the Scientific Advisory Boards of Paratus Inc., BeBiopharma Inc., Octagon Therapeutics, and AbPro Inc., all activities unrelated to the studies described here.

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Two distinct durable human class-switched memory B cell populations are induced by vaccination and infection

Affiliations

Two distinct durable human class-switched memory B cell populations are induced by vaccination and infection

Authors

Affiliations

Abstract

Conflict of interest statement

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Research Materials

Miscellaneous