The role of TIGIT+ memory B cells in immune regulation

The role of TIGIT+ memory B cells in immune regulation.  A new mechanism of regulatory B cell immunosuppression.

— Preface —

The role of regulatory B cells (Breg) in immune regulation has been widely described in different disease models, including inflammation, infectious diseases, transplantation, and cancer. However, due to the lack of Breg-specific lineage markers, the previously reported Breg subgroups are not well separated from other subgroups not only in surface phenotype, but also in functional characteristics.

Therefore, it is difficult to know which subgroups of human Breg are more important in immunomodulation. This is a key issue that needs to be resolved in the development of Breg biology and the potential clinical development of Breg-based therapeutic strategies.

The study analyzed the data of human peripheral blood and tonsil B cell FACS array, and divided the CD19+ human B cell population into 6 different populations. The study found that CD24hiCD27+CD39hiIgD−IgM+CD1c+ memory B cells exhibit powerful and unique functional characteristics in suppressing immune response. They not only express IL-10, Granzyme B and TGF-β1, but also express surface receptors PD-L1, CD39/CD73 and TIM-1. More importantly, they also express a co-inhibitory receptor TIGIT with Ig and ITIM domains, which can regulate the function of dendritic cells (DC) and inhibit Th1, Th2, Th17 and CXCR5+ICOS+T cell responses. At the same time, it promotes the response of T cells expressing IL-10. In vivo data on blood samples from liver transplant and kidney transplant recipients further support the importance of TIGIT+ human memory B cells in immune regulation.

Subgroup typing of B cells

According to the expression level of surface molecules, the study divided the peripheral blood B cells of healthy people into 6 different groups, including IgD, CD24, CD27, CD38 and CD39.

CD19+cd24hi is named population 1 (P1); IgD+B cells are divided into three different populations, CD19+CD27+CD39hiIgD+ (P2), CD19+CD27−CD39hiIgD+ (P3) and CD19+CD27−CD39loIgD+ (P5) ; IgD-B cells are divided into CD19+CD27+CD39hiIgD-(P4) and CD19+CD27-CD39+IgD-(P6) B cells.

Further characterization of the surface phenotype of the six B cell populations found that as a transitional B cell (CD24hiCD38hi), the expression of IgD and IgM on the surface of P1 increased, and the expression of CD5, CD9 and CD10 also increased, while the levels of CD39 and CD73 were low. In P2, P3, P4 and P6 subpopulations of cells. Similar to P1, P2 cells express higher levels of surface IgM than other cells. Compared with P1, P3 and P6 cells, the expression of CD1c and CD21 is also increased.

All B cells express the tested integrins, but the expression levels of P2 and P4 B cells are relatively high. The increased expression of integrin and CXCR3 in P2 and p4B cells indicates that P2 and P4 cells can migrate to target tissues better than other B cells.

P4 memory B cells highly express TIGIT and GZMB

Further research found that these P4 B cells are IgD-IgMloCD1c+CD21+CD25hi memory B cells. The analysis of the genes up-regulated in B10-like Breg cells (P2 MZ-like and P4 memory B cells) found that after CpG-B activated B cells, an increase in the expression of TIGIT in P2 MZ-like and P4 memory B cells was observed, and TIGIT may Play an important role in immune regulation.

In addition to TIGIT, the expression of GZMB levels in P2 MZ-like and P4 memory B cells also increased in response to CpG-B.

TIGIT and Granzyme B inhibit T cell response

Blocking TIGIT with anti-TIGIT antibody can partially restore the expression of IFN-γ and IL-17 when CD4+T cells are co-cultured with CpG-activated P4 memory B cells.

Granzyme B inhibitors also caused partial recovery of IFN-γ and IL-17 expression when CD4+ T cells were co-cultured with CpG-activated P1, P2, and P4 memory B cells.

In addition, although all B cell subgroups (P1–P6) express TGF-β1, P2, especially P4 memory B cells express the highest level of TGF-β1. The use of anti-TGF-β1 antibody also resulted in increased expression of IFN-γ and IL-17 in CD4+ T cells co-cultured with CpG-B-activated P4 memory B cells.

In short, P4 memory B cells further suppress the immune response by expressing the increased levels of TIGIT, granzyme B and TGF-β1.

Regulation of TIGIT+Memory B Cells on Immune Response

TIGIT expressed on Breg may act on DC cells expressing CD155. TIGIT+ memory B cells can effectively inhibit the maturation of immature monocyte-derived DC (MDDC) induced by LPS.

In addition, the IL-12A and IL-6 expressed by MDDC co-cultured with TIGIT+ memory B cells were also significantly reduced. These data indicate that TIGIT+ memory B cells can inhibit DC maturation and the expression of pro-inflammatory cytokines. Dendritic cells are the main antigen-presenting cells that can effectively induce and activate inflammation. This additional mechanism of action shown by TIGIT+ memory B cells may play a key role in immune regulation in the body.

In addition, MDDC regulated by TIGIT+memory B cells is less efficient in inducing CD4+CXCR5+ICOS+T cell responses than unregulated controls. Consistent with this, MDDC regulated by TIGIT+memory B cells induced a significant decrease in IL-21+ and IL-4+ CD4+ T cell response levels.

However, it is interesting that the CD4+ T cell response to IL-10 produced by MDDC regulated by TIGIT+ memory B cells was significantly enhanced.


These data indicate that TIGIT+ memory B cells can regulate DC cells to promote the production of IL-10 T cell responses, while inhibiting ICOS+CXCR5+ CD4+ T cell responses and the expression of IL-21 and IL-4. Therefore, TIGIT+ memory B cells may play an important role in immune regulation.

TIGIT+memory B cells in liver transplantation patients

Collect samples from patients 2-5 years after liver transplantation (N=16), and analyze the Breg subgroups in the blood of allograft recipients and found that compared with normal people and serum donor-specific antibody (DSA) negative patients In positive patients, P2 and P4 memory B cells were significantly reduced, while P1 B cells did not have a similar trend.



This indicates that regulatory B cells, especially P4 memory B cells expressing surface TIGIT, play an important role in the immune regulation of allograft patients.

Summary

TIGIT is an inhibitory receptor. TIGIT expressed on Treg promotes its inhibitory function by limiting the pro-inflammatory Th1 and Th17 response. The same inhibition of CD4+ T cells is also observed in TIGIT+ memory B cells. TIGIT on memory B cells can directly act on CD155 expressed on activated T cells, thereby inhibiting T cell responses.

In addition, TIGIT expressed on human memory B cells can also effectively inhibit the maturation of DC cells through CD155, thereby inhibiting its pro-inflammatory response. TIGIT+ memory B cells can also inhibit the expression of IL-12 and IL-6 in DC cells. Similarly, TIGIT+ memory B cells can effectively inhibit the expression of CCR7, and CCR7 is the key to DC migration to lymph nodes to initiate an immune response. These data all support the important role of TIGIT+ memory B cells in inhibiting persistent inflammation and initiating inflammation.

In short, although Breg cells can suppress T cell responses, TIGIT+Breg cells are more effective in suppressing immune responses. This is not only because they can efficiently express a variety of immunomodulatory molecules, including IL-10, PD-L1, TGF-β1 and granzyme B, etc., but also can inhibit the maturation and function of DC cells through the action of surface TIGIT. In vitro data from blood samples from patients with allogeneic liver and kidney transplants further support the importance of TIGIT+ memory B cells in immunosuppression.

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