Cheryl Rozanski

Sustained antibody responses depend on CD28 function in bone marrow-resident plasma cells.

CD28 signaling is essential for maintenance of long-term antigen-specific antibody production and for persistence of plasma cells in the bone marrow of mice.

CD28 Expressed on Malignant Plasma Cells Induces a Prosurvival and Immunosuppressive Microenvironment

Interactions between the malignant plasma cells of multiple myeloma and stromal cells within the bone marrow microenvironment are essential for myeloma cell survival, mirroring the same dependence of normal bone marrow-resident long-lived plasma cells on specific marrow niches. These interactions directly transduce prosurvival signals to the myeloma cells and also induce niche production of supportive soluble factors. However, despite their central importance, the specific molecular and cellular components involved remain poorly characterized. We now report that the prototypic T cell costimulatory receptor CD28 is overexpressed on myeloma cells during disease progression and in the poor-prognosis subgroups and plays a previously unrecognized role as a two-way molecular bridge to support myeloid stromal cells in the microenvironment. Engagement by CD28 to its ligand CD80/CD86 on stromal dendritic cell directly transduces a prosurvival signal to myeloma cell, protecting it against chemotherapy and growth factor withdrawal-induced death. Simultaneously, CD28-mediated ligation of CD80/CD86 induces the stromal dendritic cell to produce the prosurvival cytokine IL-6 (involving novel cross-talk with the Notch pathway) and the immunosuppressive enzyme IDO. These findings identify CD28 and CD80/CD86 as important molecular components of the interaction between myeloma cells and the bone marrow microenvironment, point to similar interaction for normal plasma cells, and suggest novel therapeutic strategies to target malignant and pathogenic (e.g., in allergy and autoimmunity) plasma cells.

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

In health, long-lived plasma cells (LLPC) are essential for durable protective humoral immunity, and, conversely, in disease are a major source of pathogenic Abs 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 Ab titers, by supporting the survival of LLPC, but not short-lived PC (SLPC). We now find that, unlike SLPC, CD28 activation in LLPC induces prosurvival downstream Vav signaling. Knockin mice with CD28 cytoplasmic tail mutations that abrogate Vav signaling (CD28-AYAA) had significantly fewer LLPC but unaffected SLPC numbers, whereas mice with mutations that abrogate PI3K signaling (CD28-Y170F) were indistinguishable from wild-type controls. This was consistent with the loss of CD28’s prosurvival 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 Ag-specific LLPC populations and Ab titers in vivo. Signaling downstream of the CD28 Vav motif induced previously undescribed transcriptional regulation of B lymphocyte–induced maturation protein-1, a key mediator of PC differentiation and maintenance. These findings suggest CD28 signaling in LLPC modulates the central B lymphocyte–induced maturation protein-1 transcriptional nexus involved in long-term survival and function.

CD28 - OLD DOG, NEW TRICKS: CD28 IN PLASMA CELL/MULTIPLE MYELOMA BIOLOGY

The concept of a costimulatory signal requirement for immune cell activation has been attributed to Bretscher and Cohn, 7 who first proposed that B cell activation required two signals. This model was subsequently modified by Lafferty and Cunningham for T cell activation and allograft rejection. 7 , 34 For naive T cell activation, signal one is delivered by the T cell receptor (TCR) binding to cognate antigen presented by major histocompatibility complex (MHC) molecules on professional antigen presentation cells (APCs). The second signal is delivered by costimulatory receptor binding to its ligand(s) on the APC. While the costimulatory signal alone characteristically has no effect on T cells, in combination with a signal 1 it has been clearly shown to enhance cytokine secretion, proliferation, metabolic fitness, and survival during T cell activation. The prototypic costimulatory receptor is CD28, and its effect on T cell activation has been extensively characterized. However, CD28 was also initially described to be expressed on normal plasma cells but not B cells, 29 and subsequently on the transformed counterparts of these cells (namely, multiple myeloma) – where it has been shown to be significantly associated with disease progression and poor prognosis. 14 , 52 , 56 However, plasma cells (both normal and transformed) no longer express an antigen-specific receptor to deliver a signal 1, and the biological role of CD28 in the B cell lineage has been unclear. Yet CD28 expression is highly regulated (suppressed) in B cells by Pax5, a key transcriptional regulator of mature B cell → plasma cell differentiation, 13 supporting a role for CD28 in plasma cell biology. Because multiple myeloma (MM) cells (like normal PC) are critically dependent on (largely undefined) cell–cell interactions with the bone marrow microenvironment, these interactions are central in developing new therapeutic targets for this incurable disease. This review will examine the role of CD28 expressed on PC/MM cells as a key component of this interaction.