The CD28/B7 pathway: a novel regulator of plasma cell function.

The CD28/B7 pathway is pivotal for the activation, optimal function, and regulation of T cell function. While the CD28 receptor and its ligands B7.1/B7.2 are also expressed on plasma cells, little is known of the role of the CD28/B7 pathway in plasma cell function. In this chapter we discuss the recent studies that have examined the role of CD28 expression on plasma cell function. Both stimulatory and inhibitory effects of CD28 on plasma cells have been reported. Based on our findings we propose that under homeostatic conditions the CD28/B7 interaction mediates regulation of plasma cell function whereas during inflammation this pathway can be perturbed to ramp up Ab production from existing plasma cells.

The enigma of memory B cells in malaria.

Malaria is a major public health problem particularly in the tropics. It is caused by protozoan parasites belonging to the genus Plasmodium and is transmitted by Anopheles mosquitoes. Currently, strategies to control malaria include vector control measures, chemoprophylaxis, and efficient diagnosis and treatment. The availability of a highly efficacious malaria vaccine would greatly facilitate malaria control and possibly eradicate malaria. Efforts to design such malaria vaccines are underway but are greatly hampered by the poor understanding of how immune memory to malaria is generated and maintained. In this issue of the European Journal of Immunology, Wykes and colleagues [Eur. J. Immunol. 2012. 42: 3291-3301] demonstrate that experimental malaria infection lowers the expression of B-cell-activating factor in DCs, thereby compromising the ability of these DCs to stimulate memory B cells and sustain the survival of Ab-secreting cells. These findings provide potential clues in the quest for better understanding of immunity to malaria as discussed in this Commentary.

CD28-B7 interaction modulates short- and long-lived plasma cell function.

The interaction of CD28, which is constitutively expressed on T cells, with B7.1/B7.2 expressed on APCs is critical for T cell activation. CD28 is also expressed on murine and human plasma cells but its function on these cells remains unclear. There are two types of plasma cells: short-lived ones that appear in the secondary lymphoid tissue shortly after Ag exposure, and long-lived plasma cells that mainly reside in the bone marrow. We demonstrate that CD28-deficient murine short- and long-lived plasma cells produce significantly higher levels of Abs than do their wild-type counterparts. This was owing to both increased frequencies of plasma cells as well as increased Ab production per plasma cell. Plasma cells also express the ligand for CD28, B7.1, and B7.2. Surprisingly, deficiency of B7.1 and B7.2 in B cells also led to higher Ab levels, analogous to Cd28(-/-) plasma cells. Collectively, our results suggest that the CD28-B7 interaction operates as a key modulator of plasma cell function.

Costimulation modulation uncouples protection from immunopathology in memory T cell responses to influenza virus.

The rapid effector functions and tissue heterogeneity of memory T cells facilitate protective immunity, but they can also promote immunopathology in antiviral immunity, autoimmunity, and transplantation. Modulation of memory T cells is a promising but not yet achieved strategy for inhibiting these deleterious effects. Using an influenza infection model, we demonstrate that memory CD4 T cell-driven secondary responses to influenza challenge result in improved viral clearance yet do not prevent the morbidity associated with viral infection, and they exacerbate cellular recruitment into the lung, compared with primary responses. Inhibiting CD28 costimulation with the approved immunomodulator CTLA4Ig suppressed primary responses in naive mice infected with influenza, but was remarkably curative for memory CD4 T cell-mediated secondary responses to influenza, with reduced immunopathology and enhanced recovery. We demonstrate that CTLA4Ig differentially affects lymphoid and nonlymphoid responses to influenza challenge, inhibiting proliferation and egress of lymphoid naive and memory T cells, while leaving lung-resident memory CD4 T cell responses intact. Our findings reveal the dual nature of memory T cell-mediated secondary responses and suggest costimulation modulation as a novel strategy to optimize antiviral immunity by limiting the memory T cell response to its protective capacities.

CTLA4 expression is an indicator and regulator of steady-state CD4+ FoxP3+ T cell homeostasis.

The presence of FoxP3(+) regulatory T cells (Tregs) is necessary for control of deleterious immune responses in the steady state; however, mechanisms for maintaining the frequency and quality of endogenous Tregs are not well defined. In this study, we used in vivo modulators of the CD28 and CTLA4 pathways administered to intact mice to reveal mechanisms controlling the homeostasis and phenotype of endogenous Tregs. We demonstrate that expression of the negative costimulatory regulator CTLA4 on FoxP3(+) Tregs in vivo is a direct consequence of their rapid, perpetual homeostasis. Up-regulation of CTLA4 expression occurs only on FoxP3(+) Tregs undergoing extensive proliferation and can be abrogated by inhibiting the CD28 pathway, coinciding with a reduction in FoxP3(+) Treg proliferation and frequency. We further demonstrate that CTLA4 negatively regulates steady-state Treg homeostasis, given that inhibiting CTLA4 signaling with an anti-CTLA4 blocking Ab greatly enhances Treg proliferation and overall Treg frequency. Our findings provide new insight into the origin and role of CTLA4 expression on natural FoxP3(+) Tregs and reveal opposing effects of costimulation modulators on the steady-state level and quality of Tregs, with implications regarding their effects on endogenous Tregs in patients receiving immunotherapy.