Aged B cells alter immune regulation of allografts in mice

Abstract

Organ transplantation in older people is increasing, but how aging impacts B cell responses to organ transplantation is unknown. Here, we show that the depletion of B cells with anti-CD20 antibodies has disparate effects depending on recipient age. In young murine recipients, anti-CD20 treatment impaired the ability of immune modulation to extend skin allograft survival. In contrast, anti-CD20 treatment extended allograft survival in aged recipients treated with immune modulation. Although regulatory B cell function and the numbers of marginal and follicular B cells were similar between age groups, a subpopulation of B cells, termed age-associated B cells (ABCs), accumulated upon aging. ABCs isolated from aged mice exhibited upregulation of CD73, CD80, CD106, and TLR2 and an increased capacity to augment T cell alloimmunity compared to ABCs from young mice. Importantly, ABCs from aged, but not young, mice impaired the ability of immune modulation to enhance allograft survival after adoptive transfer into young transplant recipients. Our study indicates that ABCs impair the immune regulation of allografts. Thus, recipient age needs to be considered when proposing B cell-depleting immune therapy.

CD73 expression identifies a subset of IgM+ antigen‐experienced cells with memory attributes that is T cell and CD40 signalling dependent

“…These include neutrophils, Treg cells, nodal marginal zone (nMZ) B cells, ABCs, Breg cells, B-1 B cells, CD11c + B cells and Tfh cells. 28,[34][35][36][37][38][39] We found equivalent expression of CD73 on blood neutrophils, peritoneal cavity B-1 B cells and splenic Treg cells, Breg cells and MZ B cells from WT and CD40 À/À mice (Fig. 7).…”

Aging and the immune response to organ transplantation

“…There was no alteration of regulatory B cell responses with aging; however, aged B cells exhibited enhanced priming of alloreactive B cells as compared with young B cells (86). A non-germinal zone, non-marginal zone B cell population, termed age-associated B cells (ABCs) (87), within the aged B cell pool were responsible for the enhanced T cell alloimmune priming and impaired the ability of anti-CD45Rb and anti-CD154 to prolong skin allograft survival after adoptive transfer into young mice (86). Thus, this study indicates that ABCs within the aged host may represent a barrier to immune modulation and could indicate that B cell depletion, currently used in the treatment of antibody-mediated rejection, may have disparate effects depending on host age.…”

“…In striking contrast, B cell depletion in aged mice (16-18 months of age) led to a 7-day delay in skin allograft survival (86). There was no alteration of regulatory B cell responses with aging; however, aged B cells exhibited enhanced priming of alloreactive B cells as compared with young B cells (86). A non-germinal zone, non-marginal zone B cell population, termed age-associated B cells (ABCs) (87), within the aged B cell pool were responsible for the enhanced T cell alloimmune priming and impaired the ability of anti-CD45Rb and anti-CD154 to prolong skin allograft survival after adoptive transfer into young mice (86).…”

“…The B cell pool plays disparate roles depending on host age. In a skin allograft model in which anti-CD45Rb and anti-CD154 enhance graft survival in young mice, B cell depletion led to a faster tempo to skin allograft rejection in young mice (86). In striking contrast, B cell depletion in aged mice (16-18 months of age) led to a 7-day delay in skin allograft survival (86).…”

“…In a skin allograft model in which anti-CD45Rb and anti-CD154 enhance graft survival in young mice, B cell depletion led to a faster tempo to skin allograft rejection in young mice (86). In striking contrast, B cell depletion in aged mice (16-18 months of age) led to a 7-day delay in skin allograft survival (86). There was no alteration of regulatory B cell responses with aging; however, aged B cells exhibited enhanced priming of alloreactive B cells as compared with young B cells (86).…”