Programming for T-lymphocyte fates: modularity and mechanisms

Abstract

T-cell development in mammals is a model for lineage choice and differentiation from multipotent stem cells. Although T-cell fate choice is promoted by signaling in the thymus through one dominant pathway, the Notch pathway, it entails a complex set of gene regulatory network and chromatin state changes even before the cells begin to express their signature feature, the clonal-specific T-cell receptors (TCRs) for antigen. This review distinguishes three developmental modules for T-cell development, which correspond to cell type specification, TCR expression and selection, and the assignment of cells to different effector types. The first is based on transcriptional regulatory network events, the second is dominated by somatic gene rearrangement and mutation and cell selection, and the third corresponds to establishing a poised state of latent regulator priming through an unknown mechanism. Interestingly, in different lineages, the third module can be deployed at variable times relative to the completion of the first two modules. This review focuses on the gene regulatory network and chromatin-based kinetic constraints that determine activities of transcription factors TCF1, GATA3, PU.1, Bcl11b, Runx1, and E proteins in the primary establishment of T-cell identity.

Severe and multifaceted systemic immunosuppression caused by experimental cancers of the central nervous system requires release of non-steroid soluble mediators

“…This correlated with a block in T cell proliferation at the DN2-DN3 stage. DN2-DN3 stage of T cell development is associated with high levels of proliferation following TCRβ chain selection (52). A block in DN2-DN3 is likely caused by a block in proliferation which is consistent with the most downregulated pathways analyzed by RNA-seq being involved in DNA replication and cell proliferation ( Figure 3).…”

“…We found that Rag1 and Rag2 genes, TCF3, TCF7, Gata3, and BCl11b, and Notch 1 were downregulated in thymi of GL261 tumor-bearing mice compared to controls ( Figure 3 D and S1 D). Downregulation of these genes can be consistent with a block between DN2-DN3 transition ( Figure 2 and (52,53,69,70)). Interestingly, another significantly downregulated gene in thymi of GL261-bearing mice compared to controls was Coro1a (Figure 3 Gene expression during experimental GBM induced thymic involution is not consistent with a stress response.…”

“…Using these gating strategies, we assessed the stage at which T cell development is affected by a growing glioma in the brain. Frequencies of DN1 cells were significantly increased in GL261 tumor-bearing mice compared to controls ( B cell developmental programming is actively inhibited in the normal thymus to maximize generation of functional T cells (51)(52)(53). Hence, we evaluated frequencies and numbers of thymic B cells and SP T cells that have successfully rearranged their T cell receptor using flow cytometry (Figure 2 J).…”

“…Instead, these genes were implicated mainly in pathology of neurological diseases including pain, peripheral nerve damage, and recently in Alzheimer's disease (62)(63)(64)(65)(66)(67). and Dll4 are mainly important in cTEC interaction with DN thymocytes (52). The importance of this downregulation may aid in explaining the defects seen in developing T cells rather than epithelial cells, which will be discussed below.…”

“…Additionally, we found an increase in B cell frequencies in the thymus which can be explained by a decrease in Gata3 expression. Normally, Gata3 inhibits B cell development and lineage commitment in the thymus (51)(52)(53)79). Hence, it is conceivable that during neurological injuries a decrease in Gata3 translates into an enhanced B cell development program.…”