Publications

Zhang H, Podesta MA, Cavazzoni CB, Wu Y, Lee JM, Li X, Raeder PL, Chandrakar P, Gempler M, Richardson S, Ghosh D, Sayin I, Blazar BR, Abdi R, Weins A, Chong AS, Sage PT. Follicular regulatory T cells restrain kidney allograft rejection in mice by suppressing alloreactive B cells. Nature Communications. 2025 doi: 10.1038/s41467-025-57468-4.

Pathogenic antibodies produced by alloreactive B cells mediate antibody-mediated rejection after kidney transplantation, but the mechanisms remain poorly understood. Follicular regulatory T (Tfr) cells modulate follicular helper T cell-mediated B cell responses, but the functions of Tfr in controlling alloreactive antibody are unknown. Here we study the developmental signals and functions of Tfr cells in mouse allogeneic kidney transplantation models, and show that costimulatory blockade alters the development of Tfr cells disproportionately by decreasing germinal center (GC)-like Tfr cells but increasing follicular-like Tfr cells. Functionally, global Tfr cell deletion results in accelerated graft rejection and increases in donor-specific B cells in both draining lymph nodes and kidney allografts. Mechanistically, Tfr cell deletion increases GC B cell expression of pro-inflammatory cytokines such as IL-15, while neutralization of IL-15 compensates for the loss of Tfr cells and prolongs the survival of mice receiving kidney transplants. Together our preclinical mouse data demonstrate how Tfr restrains kidney allograft rejection by limiting alloreactive B cell responses.

Allergic diseases are common and affect a large proportion of the population.  IL-13-expressing follicular T (Tfh13) cells are a newly identified population of Tfh cells that have been associated with high affinity IgE responses.  However, the origins, developmental signals, transcriptional programming and precise functions of Tfh13 cells are unknown.  Here, we examined the developmental signals for Tfh13 cells and found a direct and progressive differentiation pathway marked by the production of IL-21.  These two pathways differed in kinetics and extrinsic requirements. However, both pathways converged, forming transcriptionally similar Tfh13 cells that express the transcription factor JunB as a critical stabilizing factor.  Using an intersectional genetics-based Tfh13-DTR model to perturb these cells, we found that Tfh13 cells were essential to drive broad germinal center responses and allergen-specific IgG and IgE.  Moreover, we found that IL-21 is a broad positive regulator of allergen germinal center B cells and synergizes with IL-13 produced by Tfh13 cells to amplify allergic responses.  Thus, Tfh13 cells orchestrate multiple features of allergic inflammation.

Podesta MA, Cavazzoni CB, Hanson BL, Bechu ED, Ralli G, Clement RL, Zhang H, Chandrakar P, Lee JM, Reyes-Robles T, Abdi R, Diallo A, Sen DR, Sage PT.

Nature Communications. 2023. 14(1):7712.

In this article the Sage Lab assessed the development stages Tfh cells go through after initial differentiation to become effector Tfh cells. They found four distinct developmental stages in Tfh; Progenitor (Prog), Transitory (Trans), Fully Differentiated (Full) and Ex-Fully Differentiated (Ex). Authors also demonstrate intrinsic (FoxP1) and extrinsic (Tfr cells) factors controlling progression through these stages. This work demonstrates mechanisms controlling Tfh development and functionality and lay the framework for therapeutics to target individual Tfh stages to treat disease or enhance SARS-CoV-2 vaccines.

Zhang H, Cavazzoni CB, Podesta MA, Bechu ED, Ralli G, Chandrakar P, Lee JM, Sayin I, Tullius SG, Abdi R, Chong AS, Sage PT.

JCI Insight. 2023. Oct 23; 8(20)

In this article the Sage Lab studied developmental signals and functions of Tfh cells during allogeneic kidney transplantation. They found that Tfh undergo parallel development in LNs and kidney allografts. They also found that these Tfh cells control pathogenic B cell responses both within LNs and in kidney allografts themselves. This work provides rationale for targeting both systemic and kidney allograft B cell responses to prevent and treat antibody mediated rejection (ABMR) in the clinic.

Zhang, Hengcheng MD, PhD; Cavazzoni, Cecilia B. PhD; Hanson, Benjamin L.; Bechu, Elsa D.; Podestà, Manuel A. MD; Azzi, Jamil MD; Blazar, Bruce R. MD; Chong, Anita S. PhD; Kreisel, Daniel MD, PhD; Alessandrini, Alessandro PhD; Sage, Peter T. PhD

In this manuscript Dr. Sage’s team assessed the transcriptional programming and origins of intragraft B cells after kidney transplantation. They found that graft infiltrating B cells are innate-like transcriptionally and likely do not originate from lymph node germinal center B cells.

Transplantation 107(2):p e47-e57, February 2023. | DOI: 10.1097/TP.0000000000004398

Follicular T cells Optimize the Germinal Center Response to SARS-CoV-2 Protein Vaccination in Mice

Cavazzoni CB, Hanson BL, Podesta MA, Bechu ED, Clement RL, Zhang H, Daccache J, Reyes-Robles T, Hett EC, Vora KA, Fadeyi OO, Oslund RC, Hazuda DJ, Sage PT

Cell Reports, Feb. 2022

In this manuscript Dr. Sage’s team studied how follicular T cells control antibody responses during SARS-CoV-2 vaccination. Using genetic deletion studies and natural settings of aging they show that follicular T cells delicately balance affinity maturation and clonal expansion to optimize vaccine responses.

Paolo Fiorina et. al.

Songjie Cai ^1 2, John Y Choi ¹, Thiago J Borges ¹, Hengcheng Zhang ¹, Ji Miao ², Takaharu Ichimura ¹, Xiaofei Li ¹, Simiao Xu ², Philip Chu ¹, Siawosh K Eskandari ¹, Hazim Allos ¹, Juliano B Alhaddad ¹, Saif A Muhsin ¹, Karim Yatim ¹, Leonardo V Riella ¹, Peter T Sage ¹, Anil K Chandraker ³, Jamil R Azzi ⁴