Themis2 lowers the threshold for B cell activation during positive selection

Abstract

The positive and negative selection of lymphocytes by antigen is central to adaptive immunity and self-tolerance, yet how this is determined by different antigens is not completely understood. We found that thymocyte-selection-associated family member 2 (Themis2) increased the positive selection of B1 cells and germinal center B cells by self and foreign antigens. Themis2 lowered the threshold for B-cell activation by low-avidity, but not high-avidity, antigens. Themis2 constitutively bound the adaptor protein Grb2, src-kinase Lyn and signal transducer phospholipase γ2 (PLC-γ2), and increased activation of PLC-γ2 and its downstream pathways following B cell receptor stimulation. Our findings identify a unique function for Themis2 in differential signaling and provide insight into how B cells discriminate between antigens of different quantity and quality.

Methyltransferase Nsd2 Ensures Germinal Center Selection by Promoting Adhesive Interactions between B Cells and Follicular Dendritic Cells

“…As shown in Figure 4C, in the absence of Nsd2, the area of the cell contact zone was reduced, and the level of BCR clustering and F-actin in the contact zone were also decreased, suggesting a defective immunological synapse formation. Furthermore, we adopted an in vitro stimulation system to determine whether B cell activation by membrane antigen was affected by Nsd2 deletion (Cheng et al, 2017). 3T3 cells were engineered to express ICAM1, VCAM1, and membrane hen egg lysozyme (mHEL) on their surface (Cheng et al, 2017).…”

“…Furthermore, we adopted an in vitro stimulation system to determine whether B cell activation by membrane antigen was affected by Nsd2 deletion (Cheng et al, 2017). 3T3 cells were engineered to express ICAM1, VCAM1, and membrane hen egg lysozyme (mHEL) on their surface (Cheng et al, 2017). Nsd2 mice were crossed with MD4 transgenic mice, the BCR of which specifically recognizes HEL antigen.…”

THEMIS: Two Models, Different Thresholds

“…The other mammalian CABIT proteins have also been shown to have activating functions in receptor signaling. The B cell homologue of THEMIS, THEMIS2, lowers the threshold for B cell receptor-mediated activation by low avidity antigens and therefore has a positive role in B cell receptor signaling [30]. THEMIS and THEMIS2 are functionally interchangeable since transgenic expression of THEMIS2 rescued the developmental defect in Themis −/− mice [8].…”

Interferon γ induced compositional changes in human bone marrow derived mesenchymal stem/stromal cells

“…This is achieved by lowering the threshold for B cell activation by low-avidity, but not high-avidity, antigens [36]. However, themis2 is not required for murine B cell development, activation, or antibody responses [37].…”