PD-L1<sup>hi</sup> B regulatory cells are critical for control of the humoral immune response — ASN Events
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  3. PD-L1hi B regulatory cells are critical for control of the humoral immune response

PD-L1hi B regulatory cells are critical for control of the humoral immune response (#96)

Adnan R Khan , Emily Hams 1 , Tim Sparwasser 2 , Casey T Weaver 3 , Padraic G Fallon 1 4 5
  1. Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, CO DU, Ireland
  2. Institute of Infection Immunology, TWINCORE, Centre for Experimental and Clinical Infection Research, a Joint Venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI) , Hanover, Germany
  3. Department of Pathology, University of Alabama, Birmingham, Alabama, United States of America
  4. National Children’s Research Centre, Our Lady’s Children’s Hospital, Dublin, Co Dublin, Ireland
  5. Institute of Molecular Medicine, St. James's Hospital, Dublin, Co. Dublin, Ireland

A defining feature of the majority of B regulatory (Breg) cells described in mouse and man is their production of IL-10. However, other subsets of Breg, which act in an IL-10 independent manner, also exist. Here, we describe a distinct subset of Breg, defined by high levels of PD-L1, which can suppress inflammation.

We are able to describe the importance of PD-L1 expression on B cells in the context of humoral immunity and disease in both mouse and man. Previously, we have shown that PD-L1 on B cells is an important regulator of T follicular helper (TFH) cell activity and downstream antibody responses. Through the use of chimeric mice and transfer approaches of B cell populations with varying degrees of PD-L1 expression we now demonstrate that a PD-L1hi B cell subset dramatically suppressed humoral responses through attenuating the activation of T cells and antibody production, independent of other reported suppressor populations.

We further describe how PD-L1hi Breg are refractory to B cell depletion therapy (αCD20 mAb treatment). The suppressive capacity of these Breg was demonstrated to be dependent on PD-L1. The retention of PD-L1hi Breg, post B cell depletion therapy, was attributed to elevated expression of the B cell activating factor (BAFF) receptors BAFF-R, TACI and BCMA, which displayed enhanced uptake of BAFF compared to other B cell subsets. Blockade of BAFF-R rendered PD-L1hi B cells sensitive to B cell depletion therapy.

Together, our studies identify a previously unknown regulatory B cell that acts through the PD-1/PDL1 pathway in limiting the differentiation and function of TFH cells. It also demonstrates a novel mechanism by which B cell depletion therapy works, and thus provides insight into the dynamic control of humoral immune responses in both homeostasis and disease.