Biology subjects

Vuchkovska, A.

Publications and source records attributed to Vuchkovska, A..

3 recordsLinked to original sources

bioRxiv2022

Siglec-5 is an inhibitory immune checkpoint molecule for human T cells

Sialic acid-binding immunoglobulin-type lectins (Siglecs) are a family of immunoglobulin-type lectins that mediate protein-carbohydrate interactions via sialic acids attached to glycoproteins or glycolipids. Most of the CD33-related Siglecs (CD33rSiglecs), a major subfamily of rapidly evolving Siglecs, contain a cytoplasmic signaling domain consisting of the immunoreceptor tyrosine-based inhibitory motif (ITIM) and immunoreceptor tyrosine-based switch motif (ITSM) and mediate suppressive signals for lymphoid and myeloid cells. While most CD33rSiglecs are expressed by innate immune cells, such as monocytes and neutrophils, to date, the expression of Siglecs in human T cells has not been well appreciated. In this study, we found that Siglec-5, a member of the CD33rSiglecs, is expressed by most activated T cells upon antigen receptor stimulation. Functionally, Siglec-5 suppresses T cell activation. In support of these findings, we found that Siglec-5 overexpression abrogates antigen receptor induced activation of Nuclear factor of activated T cells (NFAT) and Activator protein 1 (AP-1). Furthermore, we show that GBS {beta}-protein, a known bacterial ligand of Siglec-5, reduces the production of cytokines and cytolytic molecules by activated primary T cells in a Siglec-5 dependent manner. Our data also show that some cancer cell lines express a putative Siglec-5 ligand(s), and that the presence of soluble Siglec-5 enhances tumor-cell specific T cell activation, suggesting that some tumor cells inhibit T cell activation via Siglec-5. Together, our data demonstrate that Siglec-5 is a previously unrecognized inhibitory T cell immune checkpoint molecule and suggests that blockade of Siglec-5 could serve as a new strategy to enhance anti-tumor T cell functions. One Sentence SummarySiglec-5 is a novel checkpoint receptor expressed by activated human T cells that antagonizes TCR mediated activation and suppresses T cell effector functions such as cytokine production.

immunology↗

bioRxiv2018

CD36hi monocytes play immunoregulatory roles in human umbilical cord blood

The fetal and neonatal immune systems are uniquely poised to generate tolerance to self, maternal, and environmental antigens encountered in the womb and shortly after birth. The tolerogenic nature of fetal and neonatal immunity is a rising health concern with the spread of vertically transmitted viruses, such as the Zika virus. A variety of mechanisms contribute to fetal and neonatal tolerance, including a propensity to generate Foxp3+ regulatory T cells (Tregs). Here, we demonstrate that a subset of CD14+ monocytes expressing the scavenger molecule, CD36, is able to generate CD4+ and CD8+ T cells that express Foxp3 from umbilical cord blood (UCB). Monocyte-induced Foxp3+ T cells have potent suppressive functions on T cell proliferation and maintain Foxp3 expression over six weeks in vitro. Importantly, UCB-derived Foxp3+ T cells are distinguishable from adult peripheral blood (APB) CD4+CD25+ Tregs by surface antigen expression. While UCB-derived Foxp3+ T cells express prototypic Treg-associated surface antigens, such as CD25 and glucocorticoid-induced tumor necrosis factor-related receptor (GITR), only UCB-derived Foxp3+ T cells express CD26. In addition, most UCB-derived CD8+Foxp3+ T cells express CD31. Mechanistically, both APB and UCB-derived monocytes support the development of Foxp3+ T cells from naive T cells, but APB naive T cells are less efficient in expressing Foxp3 than UCB naive T cells. These data suggest that antigen presentation by CD36hi monocytes in the fetus leads to the development of a group of T cells that share some but not all phenotypes of adult thymus-derived Tregs.

immunology↗

bioRxiv2018

Molecular Genetic Analysis of Rbm45/Drbp1: Genomic Structure, Expression, and Evolution

RNA recognition motif-type RNA-binding domain containing proteins (RBDPs) participate in RNA metabolism including regulating mRNA stability, nuclear-cytoplasmic shuttling, and splicing. Rbm45 is an RBDP first cloned from rat brain and expressed spatiotemporally during rat neural development. More recently, RBM45 has been associated with pathological aggregates in the human neurological disorders amyotrophic lateral sclerosis, frontotemporal lobar degeneration, and Alzheimers. Rbm45 and the neural developmental protein musashi-1 are in the same family of RDBPs and have similar expression patterns. In contrast to Musashi-1, which is upregulated during colorectal carcinogenesis, we found no association of RBM45 overexpression in human colon cancer tissue. In order to begin characterizing RNA-binding partners of Rbm45, we have successfully cloned and expressed human RBM45 in an Intein fusion-protein expression system. Furthermore, to gain a better understanding of the molecular genetics and evolution of Rbm45, we used an in silico approach to analyze the gene structure of the human and mouse Rbm45 homologues and explored the evolutionary conservation of Rbm45 in metazoans. Human RBM45 and mouse Rbm45 span {bsim}17 kb and 13 kb, respectively, and contain 10 exons, one of which is non-coding. Both genes have TATA-less promoters with an initiator and a GC-rich element. Downstream of exon 10, both homologues have canonical polyadenylation signals and an embryonic cytoplasmic polyadenylation element. Moreover, our data indicate Rbm45 is conserved across all metazoan taxa from sponges (phylum Porifera) to humans (phylum Chordata), portending a fundamental role in metazoan development.

genetics↗