No abstract

In response to infection, naïve CD4 T cells differentiate into two subpopulations: T follicular helper (T) cells, which support B cell antibody production, and non-T cells, which enhance innate immune cell functions. Interleukin-2 (IL-2), the major cytokine produced by naïve T cells, plays an important role in the developmental divergence of these populations. However, the relationship between IL-2 production and fate determination remains unclear. Using reporter mice, we found that differential production of IL-2 by naïve CD4 T cells defined precursors fated for different immune functions. IL-2 producers, which were fated to become T cells, delivered IL-2 to nonproducers destined to become non-T cells. Because IL-2 production was limited to cells receiving the strongest T cell receptor (TCR) signals, a direct link between TCR-signal strength, IL-2 production, and T cell fate determination has been established.

Both deletion and anergy shape B cell tolerance to membrane-bound antigens.

Rheumatoid arthritis develops in association with a defect in peripheral CD4+ T cell homeostasis. T cell lymphopenia has also been shown to be a barrier to CD4+ T cell clonal anergy induction. We, therefore, explored the relationship between clonal anergy induction and the avoidance of autoimmune arthritis by tracking the fate of glucose-6-phosphate isomerase (GPI)-reactive CD4+ T cells in the setting of selective T cell lymphopenia. CD4+ T cell recognition of self GPI peptide/MHCII complexes in normal murine hosts did not lead to arthritis, and instead caused those T cells to develop a Folate receptor 4 (FR4)hi CD73hi anergic phenotype. In contrast, hosts selectively depleted of polyclonal Foxp3+ CD4+ T regulatory cells could not make GPI-specific CD4+ T cells anergic, and failed to control arthritis. This suggests that autoimmune arthritis develops in the setting of lymphopenia when Foxp3+ CD4+ T regulatory cells are insufficient to functionally inactivate all autoreactive CD4+ T cells that encounter self Ag.

B cells provide humoral immunity by differentiating into antibody-secreting plasma cells, a process that requires cellular division and is linked to DNA hypomethylation. Conversely, little is known about how de novo deposition of DNA methylation affects B cell fate and function. Here we show that genetic deletion of the de novo DNA methyltransferases Dnmt3a and Dnmt3b (Dnmt3-deficient) in mouse B cells results in normal B cell development and maturation, but increased cell activation and expansion of the germinal center B cell and plasma cell populations upon immunization. Gene expression is mostly unaltered in naive and germinal center B cells, but dysregulated in Dnmt3-deficient plasma cells. Differences in gene expression are proximal to Dnmt3-dependent DNA methylation and chromatin changes, both of which coincide with E2A and PU.1-IRF composite-binding motifs. Thus, de novo DNA methylation limits B cell activation, represses the plasma cell chromatin state, and regulates plasma cell differentiation.