Early Development in the Peritoneal Cavity of CD49dhigh Th1 Memory Phenotype CD4+ T Cells with Enhanced B Cell Helper Activity

Abstract

The Th cells that regulate peritoneal B-1 cell functions have not yet been well characterized. To address this question, we investigated peritoneal CD4+ T cells, observed a high frequency of the conjugates of B-CD4+ T cells in the peritoneal cavity, and identified a population of CD49dhighCD4+ T cells that constituted about half of all CD4+ T cells in the peritoneal cavity, but were rarely found in other compartments. Peritoneal CD49dhighCD4+ T cells were CD44highCD62Llow; expressed integrin α4β1 and CXCR3; and rapidly secreted IFN-γ, TNF-α, and IL-2, showing features of proinflammatory Th1 cells. Peritoneal CD49dhighCD4+ T cells developed spontaneously, were detected at the age of 12 d, and showed stem cell–like properties. Their development was observed in mice deficient for signaling lymphocytic activation molecule-associated protein, but not in athymic nude mice and mice lacking in expression of MHC class II on thymic epithelial cells. Peritoneal CD49dhighCD4+ T cells were more resistant to irradiation and more sensitive to NAD-induced cell death than CD49dlowCD4+ T cells. Notably, peritoneal CD49dhighCD4+ T cells also showed some characteristics of follicular Th cells, such as the expression of programmed cell death 1, ICOS, IL-21, and CXCR5. Moreover, peritoneal CD49dhighCD4+ T cells enhanced the secretion of IgM Abs by B-1a cells and IgG Abs by splenic B cells. These data suggest that peritoneal CD49dhighCD4+ T cells may be innate-like CD4+ T cells, which develop early and have a dual capacity to support both humoral and cellular immunity.

Intestinal helminth infection induces highly functional resident memory CD4+ T cells in mice

“…Access to the peritoneum from the circulation preferentially occurs through omental milk spots in an α4β7-dependent fashion, whereas entry to the peritoneal cavity is mediated by α4β1 as shown for B cells [44] and T cells [45]. Of note, almost all PCderived Th2 memory cells do express CD49d (subunit α4), which was also shown for PC-derived Th1 memory phenotype of CD4 + T cells [46]. CD49d can pair with β1 (not investigated in this study) or β7 (almost 50% of GATA3 + T cells express the integrin β7), and could have enabled the access of these cells to the PC.…”

T follicular helper cell programming by cytokine‐mediated events

“…For example, although Tfh cells develop during the initial response to antigen through the events described above, it has also been shown that additional effector T helper cell subsets are capable of up‐regulating a Tfh‐like gene expression profile, making alternative Tfh developmental pathways plausible as well (Fig. ) . Similarly, studies have provided compelling evidence to suggest that differentiated Tfh cells are capable of up‐regulating gene expression programmes associated with alternative T helper cell types .…”

“…1). [24][25][26][27] Similarly, studies have provided compelling evidence to suggest that differentiated Tfh cells are capable of up-regulating gene expression programmes associated with alternative T helper cell types. [28][29][30] Furthermore, it has been demonstrated that these multidirectional plasticity events in T helper cell populations are due in large part to an 'accessible' chromatin structure present at gene loci encoding key lineage-defining transcription factors, including Bcl-6.…”

IL-7 signalling represses Bcl-6 and the TFH gene program

“…Given the inherent complexity of this process, many questions remain regarding the genesis of T FH cell populations. For example, while T FH cells can and do develop during the initial response to antigen, it has also been demonstrated that other effector T-helper cell subsets are capable of adopting a T FH -like profile, making a ‘post-effector' developmental pathway plausible as well 8 9 10 11 12 13 . These previous studies are important as they support the possibility that, in addition to effector T FH cells, other T-helper populations may assist in long-term antibody-mediated immunity by co-opting certain aspects of the T FH -cell gene program.…”