Function of Siglec 5 in T cell activation.

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Group B Streptococcus (GBS ) is a common commensal bacterium for healthy adults. Approximately 20% of women are infected with GBS in the genitourinary tract without symptoms. However, GBS can cause serious disease in newborn infants. A majority of newborn infants from colonized women get infected with GBS, and about 1% of these infants develop sepsis. Indeed, GBS is a leading cause of invasive infections in infants. GBS infection can be lethal for preterm babies. Moreover, approximately 50% of GBS meningitis survivors suffer lifelong neurological impairment. Thus, it is critically important to understand how GBS colonizes infants and what causes invasive infection by GBS to improve the health care of newborns. Infants have a suppressed immune system which makes them highly vulnerable to infections and limits their immune responses to protective and life-saving vaccines. Both adaptive and innate immune responses in the infant are less effective than those in adult. However, how infant immunity differs from adult immunity in understudies and requires more investigations. GBS has unique capabilities to modulate the human immune system. One such mechanism is the immune inhibition by GBS's cell wall-anchored β–protein. This protein binds to a complement regulatory factor H and the constant region of IgA. Moreover, the GBS β protein binds a C-type Sialic acid-binding immunoglobulin-like lectin 5 (Siglec) 5. Siglec 5 is a cell surface protein expressed by many types of myeloid cells and has a cytoplasmic domain with two immunosuppressive motifs: immunoreceptor tyrosine-based inhibitory motif (ITIM) and immunoreceptor tyrosine-based switch motif (ITSM). Siglec 5 was shown to suppress activation of neutrophils and macrophages but was reported previously not expressed by human T cells. Importantly, our sequence alignment analysis showed that the cytoplasmic region of Siglec 5 is closely related to a prototypic immune checkpoint molecule PD-1. To test if GBS modulates perinatal immune responses by β protein-Siglec 5 interactions, we examined the expression of Siglec 5 by cord blood cells in our preliminary study. Unlike previous reports, our data show that a majority of activated cord blood and adult blood T cells express Siglec 5. Siglec 5 expressions in a T cell line inhibited antigen receptor-induced activation of transcription factors. Moreover, recombinant GBS β protein suppressed primary T cell responses, especially Th1 type cytokine productions. Thus, Siglec 5 is a potential immune checkpoint molecule that was not previously recognized. Based on these data, we hypothesize that GBS inhibits activation of perinatal T cells upon infection by β protein-Siglec 5 interactions and reduces adaptive immune responses. In this study, we aim to pursue the following two questions. (1) How does the GBS β protein change T cell activation? (2) Is Siglec 5 required for the T cell suppression by GBS-β protein?