Prolonged physical interaction between helper T cells and antibody-producing B cells is crucial for efficient immune responses. Mutations in a protein that underlies this process cause human disease.
The production of antibodies by B cells is essential for protective immunity following vaccination or exposure to infectious pathogens. The development of antibody-secreting B cells occurs in discrete areas of lymphoid tissues called germinal centres1,2, the formation of which depends on interactions between B cells and T cells bearing the CD4 molecule on their surface (CD4+ T cells). But several steps in the orchestration of T- and B-cell activation, differentiation and 'homing' to germinal centres during an immune response remain incompletely defined. For example, mutations in the protein SAP, which is involved in signalling by the SLAM family of cell-surface receptors3, leads to defects in the formation of germinal centres and the generation of long-lived antibody-secreting B cells. These defects result in a human immunodeficiency condition called X-linked lymphoproliferative disease3. But the mechanism associated with loss of SAP function has remained unknown. On page 764 of this issue, Qi et al.4 shed light on how SAP functions in CD4+ T cells to efficiently engage B cells and to provide appropriate signals for both the formation of germinal centres and the differentiation of B cells into antibody-secreting cells.
Several specialized immune cells mediate B-cell differentiation into long-lived antibody-secreting cells. Initially, dendritic cells capture foreign antigens and present them to CD4+ T cells, thereby activating them1,2. These antigen-specific CD4+ T helper cells then interact with antigen-specific B cells, which undergo intense proliferation and eventually differentiate into long-lived antibody-secreting cells (Fig. 1). Qi et al. show that SAP is not required for dendritic cells to bind to and activate CD4+ T cells. Instead, the authors find that SAP-deficient, activated T cells cannot form stable interactions with B cells. The reduction in contact time between T and B cells probably explains the failure of SAP-deficient CD4+ T cells to deliver the necessary contact-mediated helper signals to B cells.
The authors also find that activated SAP-deficient CD4+ T cells show characteristics of functional follicular helper T (TFH) cells, which are normally found in the germinal centres5. For instance, like TFH cells, CD4+ T cells from SAP-deficient mice express high levels of specific surface molecules, including CXCR5, ICOS, CD40L and OX40. Nonetheless, these cells fail to efficiently enter or remain within germinal centres — a central requirement for a TFH cell to fulfil its duty of helping B cells5,6. So, in X-linked lymphoproliferative disease, defects in germinal-centre formation and antibody production seem to be due not only to inadequate communication between T and B cells but also to failed homing of TFH cells to the germinal centres.
These findings have two noteworthy implications. First, they indicate that CD4+ T cells use different sets of molecules for each of the cell types with which they communicate and interact. Specifically, SAP — and, by inference, the SLAM family of cell-surface receptors — is required for the dialogue between CD4+ T cells and B cells but not for that between T cells and dendritic cells. Indeed, increased expression of specific SLAM proteins (CD84, SLAM, Ly108 and CD229) on B cells but not on dendritic cells4 supports this conclusion.
Second, the data4 suggest that the array of molecules involved in the dialogue between dendritic cells and T cells is insufficient to induce functional TFH cells. Instead, it seems that B cells provide a unique signal that allows the appropriate CD4+ T cells to become fully functional TFH cells — an idea supported by work in B-cell-deficient mice7. By inference, therefore, the definition of TFH cells should be refined beyond their expression of molecules such as CXCR5. Indeed, earlier studies6,8 noted that the population of CXCR5-expressing cells includes CD4+ T cells found not only in germinal centres, but also outside them. Future work should determine the contributions of these different CXCR5-expressing CD4+ T-cell populations to B-cell responses and identify more specifically the TFH cells that are truly located in germinal centres.
SAP binds to the cytoplasmic domain of SLAM-family cell-surface receptors. A crucial question arising from Qi and colleagues' study4 is which SLAM members are required for optimal adhesion of T cells to B cells. Although SLAM and CD229 are highly expressed on B cells, their deletion does not impair germinal-centre formation or T-cell-dependent antibody responses9,10. CD84, however, could be a promising candidate, as it is highly expressed on both TFH and B cells3,4,5,11. So (presumably SAP-dependent) interactions between CD84 molecules on these cells might contribute to the formation of stable conjugates between TFH and germinal-centre B cells, which seem to be essential for the efficient production of antibodies. Generation of CD84-deficient mice will clarify the role of this receptor in mediating interactions between T and B cells.
How does SAP itself contribute to adhesion between T and B cells? SAP-dependent signalling downstream of the SLAM-family receptors may induce changes in the expression of other adhesion molecules, such as integrins, that are involved in interactions between T and B cells. But the introduction of a signalling-deficient version of SAP into SAP-deficient CD4+ T cells can restore adhesion between B and T cells4 — an observation that hints that signalling through SAP-associating receptors per se is not required for normal interactions between these cells. Alternatively, SLAM-family members may operate as adhesion molecules only in the presence of functional SAP (ref. 3). In other words, although SAP is unlikely to regulate the expression levels of SLAM receptors, it might stabilize interactions between these receptors on B cells and CD4+ T cells.
In mice, genes encoding SLAM-family receptors lie in a region known to be associated with susceptibility to the autoimmune disease systemic lupus erythematosus12. So Qi and colleagues' results also have potential implications for understanding autoimmune diseases. Variations in the genes encoding SLAM proteins are predicted12 to influence the strength of interactions between the extracellular domains of these cell-surface receptors or between their cytoplasmic domains and SAP. If reduced adhesion between B cells and SAP-deficient TFH cells contributes to immunodeficiency, as occurs in X-linked lymphoproliferative disease, the converse — prolonged interactions between T and B cells through increased binding strength — might result in amplified T-cell help and abnormal antibody responses characteristic of autoimmunity. By revealing more of the steps in the intricate dance of collaboration between T and B cells leading to antibody production, this study4 provides potential routes for modulating aberrant immunity in both immunodeficiency and autoimmunity.
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Annals of the New York Academy of Sciences (2012)
Early commitment of naïve human CD4+ T cells to the T follicular helper (TFH ) cell lineage is induced by IL-12
Immunology and Cell Biology (2009)