Abstract
Break of B cell tolerance to self-antigens results in the development of autoantibodies and, thus, leads to autoimmunity. How B cell tolerance is maintained during active germinal center (GC) reactions is yet to be fully understood. Recent advances revealed several subsets of T cells and B cells that can positively or negatively regulate GC B cell responses in vivo. IL-21-producing CXCR5+ CD4+ T cells comprise a distinct lineage of helper T cells—termed follicular helper T cells (TFH)—that can provide help for the development of GC reactions where somatic hypermutation and affinity maturation take place. Although the function of TFH cells is beneficial in generating high affinity antibodies against infectious agents, aberrant activation of TFH cell or B cell to self-antigens results in autoimmunity. At least three subsets of immune cells have been proposed as regulatory cells that can limit such antibody-mediated autoimmunity, including follicular regulatory T cells (TFR), Qa-1 restricted CD8+ regulatory T cells (CD8+TREG), and regulatory B cells (BREG). In this review, we will discuss our current understanding of GC B cell regulation with specific emphasis on the newly identified immune cell subsets involved in this process.
Highlights
Negative selection during the development of B cells in the bone marrow and T cells in the thymus leads to the deletion of self-reactive B and T cells
It has been reported that CD40 ligand (CD40L) together with IL-21 or IL-4 is required for the maintenance of germinal center (GC) B cells
The diverse types of immune cells involved in GC B cell responses reflect an orchestrated regulation of this process
Summary
Negative selection during the development of B cells in the bone marrow and T cells in the thymus leads to the deletion of self-reactive B and T cells. Some of the self-reactive B cells can escape from negative selection in the bone marrow, they are seldom activated due to the lack of proper help from T cells, since most of self-reactive T cells in the periphery are in an anergic state These processes—termed central and peripheral tolerance—represent a primary mechanism by which the immune system prevents the development of autoimmunity. The somatic hypermutation process is a double-edged sword that may lead to the generation of high affinity antibodies, as well as auto-reactive B cells in the periphery. This T: B interaction mainly occurs in a specialized region of B cell area, termed germinal center (GC). Understanding how TFH cells and these regulatory cells control GC B cell responses will pave the way for the development of novel therapeutic targets in vaccine design, as well as for the treatment of antibody-mediated autoimmune diseases
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