SAP is required for generating long-term humoral immunity

Abstract

Long-lived plasma cells and memory B cells are the primary cellular components of long-term humoral immunity and as such are vitally important for the protection afforded by most vaccines. The SAP gene has been identified as the genetic locus responsible for X-linked lymphoproliferative disease, a fatal immunodeficiency. Mutations in SAP have also been identified in some cases of severe common variable immunodeficiency disease. The underlying cellular basis of this genetic disorder remains unclear. We have used a SAP knockout mouse model system to explore the role of SAP in immune responses. Here we report that mice lacking expression of SAP generate strong acute IgG antibody responses after viral infection, but show a near complete absence of virus-specific long-lived plasma cells and memory B cells, despite the presence of virus-specific memory CD4+ T cells. Adoptive transfer experiments show that SAP-deficient B cells are normal and the defect is in CD4+ T cells. Thus, SAP has a crucial role in CD4+ T-cell function: it is essential for late B-cell help and the development of long-term humoral immunity but is not required for early B-cell help and class switching.

The darker side of follicular helper T cells: from autoimmunity to immunodeficiency

“…61 Similarly, mice deficient in SAP show severe functional defects in CD4 1 T cells as evidenced by their inability to confer long-lived humoral responses. 62 Studies further demonstrate that CD4 1 T-cell function in HIGM patients, which lack CD40L, is strictly compromised. 63 T FH CELLS AND LYMPHOMA Emerging evidence supports the relationship between T FH cells and lymphoma, particularly peripheral T-cell lymphoma (PTCL).…”

Perturbation of B Cell Activation in SLAM-Associated Protein-Deficient Mice Is Associated with Changes in Gammaherpesvirus Latency Reservoirs

“…SAP-deficient mice have defective Th2 cell development and abnormal Ig classswitching (20, 21, 24 -27). In addition, they generate reduced numbers of germinal centers and memory B cells (20,21,(27)(28)(29), which may be due both to impaired CD4 T cell function as well as intrinsic B cell defects (27)(28)(29)(30). SAP-deficient mice have also been reported to develop enhanced Th1 responses characterized by excessive IFN-␥ production, and exaggerated CTL activity (20,21,29,31,32).…”

“…In addition, they generate reduced numbers of germinal centers and memory B cells (20,21,(27)(28)(29), which may be due both to impaired CD4 T cell function as well as intrinsic B cell defects (27)(28)(29)(30). SAP-deficient mice have also been reported to develop enhanced Th1 responses characterized by excessive IFN-␥ production, and exaggerated CTL activity (20,21,29,31,32). As a consequence of the complex effects on signaling, SAP-deficient mice have been shown to have perturbations in both cellular and humoral immunity in response to a variety of infections (20,21,27,29,33).…”

“…SAP-deficient mice have also been reported to develop enhanced Th1 responses characterized by excessive IFN-␥ production, and exaggerated CTL activity (20,21,29,31,32). As a consequence of the complex effects on signaling, SAP-deficient mice have been shown to have perturbations in both cellular and humoral immunity in response to a variety of infections (20,21,27,29,33).…”

“…B cell activation and function have been shown to be impaired in SAP-deficient mice, manifest by reduced numbers of germinal centers and failure to generate class-switched Abs and memory B cells following infection with a variety of pathogens (20 -22, 28, 29, 33). There is evidence to suggest that both inherent B cell defects and defects in CD4 T cells contribute to the impaired B cell function (27)(28)(29)(30). Infection with ␥HV68 induces a striking splenomegaly, due to concordant increases in splenic B and T cells (44), and a strong CD4-dependent polyclonal B cell response (45).…”