CD28 Promotes Plasma Cell Survival, Sustained Antibody Responses, and BLIMP-1 Upregulation through Its Distal PYAP Proline Motif

Abstract

In health, long-lived plasma cells (LLPC) are essential for durable protective humoral immunity, and conversely in disease are a major source of pathogenic antibodies in autoimmunity, graft rejection and allergy. However, the molecular basis for their longevity is largely unknown. We have recently found that CD28 signaling in plasma cells (PC) is essential for sustaining antibody titers, by supporting the survival of LLPC but not short-lived PC (SLPC). We now find that unlike SLPC, CD28 activation in LLPC induces pro-survival downstream Vav signaling. Knock-in mice with CD28 cytoplasmic tail mutations that abrogate Vav signaling (CD28-AYAA) had significantly fewer LLPC but unaffected SLPC numbers, while mice with mutations that abrogate PI3K signaling (CD28-Y170F) were indistinguishable from WT controls. This was consistent with the loss of CD28’s pro-survival effect in LLPC from CD28-AYAA, but not CD28-Y170F, mice. Furthermore, the CD28 Vav motif in the B lineage was essential for the long-term maintenance of antigen-specific LLPC populations and antibody titers in vivo. Signaling downstream of the CD28 Vav motif induced previously undescribed transcriptional regulation of BLIMP-1, a key mediator of PC differentiation and maintenance. These findings suggest CD28 signaling in LLPC modulates the central BLIMP-1 transcriptional nexus involved in long-term survival and function.

Delayed Cytotoxic T Lymphocyte–Associated Protein 4–Immunoglobulin Treatment Reverses Ongoing Alloantibody Responses and Rescues Allografts From Acute Rejection

“…Nevertheless, we observed a trend towards a more rapid decline the DSA at day 42, raising the possibility that CTLA4-Ig may inhibit antibody production by plasma cells (Fig 1B). Indeed, Lee and colleagues [41, 42] have reported that long-lived plasma cells resident in the bone marrow require CD28-B7 interactions for their survival. Thus, a more careful analysis of the impact of CTLA4-Ig on long-lived plasma cells is required, as there continues to be a strong clinical need to identify drugs that can reverse established DSA responses.…”

CD86 regulates myeloma cell survival

“…4 The signals downstream of CD28 activation have been thoroughly investigated in T cells; however, the downstream mediators in plasma cells are only beginning to be characterized. [5][6][7] CD28 is expressed in the subset of bone marrow cells to which the most long-lived fraction of human plasma cells belong 8 and has been reported to be a poor prognostic indicator for patients with myeloma. It is highly expressed at diagnosis in patients with MAF translocations, and expression correlates with disease progression.…”

The impact of belatacept on third-party HLA alloantibodies in highly sensitized kidney transplant recipients

“…5,6 In addition, in a dual therapy setting including bortezomib, belatacept suppressed memory B cell proliferation. 7,8 Furthermore, studies in healthy human volunteers demonstrated CD28 expression on approximately 30% of LLPC. Interestingly, murine studies revealed that CD28 is important for LLPC survival and maintenance of long-term antibody titers.…”

“…Interestingly, murine studies revealed that CD28 is important for LLPC survival and maintenance of long-term antibody titers. 7,8 Furthermore, studies in healthy human volunteers demonstrated CD28 expression on approximately 30% of LLPC. 9 Finally, recent studies revealed decreased production of de novo donor-specific HLA antibodies (DSA) 10,11 and elimination of preexisting DSA 12 in minimally sensitized recipients treated with belatacept compared to those patients treated with cyclosporine.…”