Attenuated germinal center (GC) reactions in Sphingosine-1-Phosphate Receptor 4 (S1PR4) knockout mice still produce high-affinity antibodies despite severe deficiencies

Authors

• KC Robichaux
• AN Henning
• V de Giorgi

Abstract

Sphingosine-1-Phosphate (S1P) is a lipid that exists in strict biological gradients to direct vital homeostatic functions such as lymphocyte re-circulation. In addition, S1P supports processes during immune activation, such as retention of germinal center (GC) B cells. While these examples are controlled through other well-studied members of the S1P receptor (S1PR1-5) family, little is known about the role of S1PR4 in immunity. In a TH1 footpad immunization model, S1PR4-/- mice developed attenuated immune responses that lacked the robust proliferative burst of B cells, which is characteristic of the peak of a GC reaction. Flow cytometric analysis revealed key populations, including T follicular helper (TFH) and GC B cells, were strikingly diminished in KO mice. Interestingly, at later time-points the GC B cell population ultimately achieved comparable levels to WT despite initial deficiencies and without the recovery of TFH cell numbers. Because GC reactions are considered the main mechanism underlying antigen (ag)-specific antibody production, we evaluated the humoral response and found similar levels of total and ag-specific IgG isotypes. This was unexpected because KO GC B cells had developed among fewer TFH cells to facilitate affinity maturation and isotype switching. While histological analysis confirmed the phenotypic findings, it also provided important insight into the lymphoid architecture. In particular, we noticed abnormal localization of CD31+ endothelium within KO follicular B cell areas, rather than within the T cell cortex. Through on-going studies, we are working to tie these inappropriate vascular entry points to the deficient immune response observed in S1PR4-/- mice.

Scientific Focus Area: Immunology

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