Angiotensin receptor blockers modulate the lupus CD4+ T cell epigenome characterized by TNF family-linked signaling.

In systemic lupus erythematosus (lupus), environmental effects acting within a permissive genetic background lead to autoimmune dysregulation. Dysfunction of CD4+ T cells contributes to pathology by providing help to autoreactive B and T cells, and CD4+ T cell dysfunction coincides with altered DNA methylation and histone modifications of select gene loci. However, chromatin accessibility states of distinct T cell subsets and mechanisms driving heterogeneous chromatin states across patients remain poorly understood.

PD-1 and CTLA-4 exert additive control of effector regulatory T cells at homeostasis.

At homeostasis, a substantial proportion of Foxp3 T regulatory cells (T) have an activated phenotype associated with enhanced TCR signals and these effector T cells (eT) co-express elevated levels of PD-1 and CTLA-4. Short term blockade of the PD-1 or CTLA-4 pathways results in increased eT populations, while combination blockade of both pathways had an additive effect. Mechanistically, combination blockade resulted in a reduction of suppressive phospho-SHP2 Y580 in eT cells which was associated with increased proliferation, enhanced production of IL-10, and reduced dendritic cell and macrophage expression of CD80 and MHC-II.

Helios and RORγt Treg populations are differentially regulated by MHCII, CD28, and ICOS to shape the intestinal Treg pool.

Foxp3 regulatory T cells (Tregs) are essential for intestinal homeostasis. Tregs in the small intestine include Helios thymus-derived Tregs (tTregs) and RORγt Tregs that differentiate in the periphery after antigenic stimulation (pTregs). TCR and costimulatory signals sustain Tregs with effector phenotypes, including those in the intestine, but it is unknown if tTregs and pTregs have similar requirements for these pathways.

PD-L1-PD-1 interactions limit effector regulatory T cell populations at homeostasis and during infection.

Phenotypic and transcriptional profiling of regulatory T (T) cells at homeostasis reveals that T cell receptor activation promotes T cells with an effector phenotype (eT) characterized by the production of interleukin-10 and expression of the inhibitory receptor PD-1. At homeostasis, blockade of the PD-1 pathway results in enhanced eT cell activity, whereas during infection with Toxoplasma gondii, early interferon-γ upregulates myeloid cell expression of PD-L1 associated with reduced T cell populations. In infected mice, blockade of PD-L1, complete deletion of PD-1 or lineage-specific deletion of PD-1 in T cells prevents loss of eT cells.

A review of signaling and transcriptional control in T follicular helper cell differentiation.

T follicular helper (Tfh) cells are a critical component of adaptive immunity and assist in optimal Ab-mediated defense. Multiple effector functions of Tfh support germinal center B cell survival, Ab class switching, and plasma cell maturation. In the past 2 decades, the phenotype and functional characteristics of GC Tfh have been clarified allowing for robust studies of the Th subset including activation signals and environmental cues controlling Tfh differentiation and migration during an immune response.