Reversal of the TCR Stop Signal by CTLA-4

Abstract

A myosin for RNA Pol II T ranscription gets a boost from myosin VI, according to fi ndings from Sarah Vreugde (DIBIT Scientifi c Institute, Milano, Italy) and colleagues. The motor might drag genes into transcription neighborhoods. While trying to understand the function of myosin VI, Vreugde noticed that its localization pattern looked much like that of RNA polymer-ase II. The authors then showed an association between the motor and polymerase that depends on ongoing transcription. By cross-linking myosin VI to chromatin, the group identifi ed several genes at which the motor is found. The mRNA levels of these genes decreased when myosin VI levels were reduced. Vreugde next hopes to inhibit just the nuclear pool of myosin VI and then do genome-wide analyses to identify more affected genes. Assuming its infl uence is widespread, the motor might spool the DNA past aggregates of RNA polymerases or recruit stretches of DNA to transcription factories. "DNA recruitment to transcription factories would be heavy work," says Vreugde. "But myosin is well-suited to accomplish that." Whether its unusual preference to move toward actin minus ends helps myosin VI at all is unclear, as the polarity of the nuclear actin network is not known and probably dynamic. The only other known nuclear myosin, myosin I, is plus-end directed but still enhances transcription by all the RNA polymerases.

Abnormal CTLA‐4 function in T cells from patients with systemic lupus erythematosus

“…Furthermore lupus T cells demonstrate more rapid formation of a stable immunological synapse [17,18], which is normally inhibited by CTLA-4 [19]. We reasoned, therefore, that CTLA-4 maybe defective in its ability to inhibit activation in lupus T cells.…”

Emerging patterns of risk factor make‐up enable subclassification of rheumatoid arthritis

“…Additionally, observations from a recent study support a distinct mechanism that is based on limited contact time between antigen-presenting cells and T cells. Schneider et al (38) observed that CTLA-4 signaling results in higher motility of T cells in lymph nodes and thereby leads to diminished ability of T cells to interact with professional antigen-presenting cells, and thus to reduced T cell activation (38). Because CTLA4 polymorphisms have been associated with several immune diseases, CTLA4 seems to be a general susceptibility locus for autoimmunity, most likely through an altered ability to dampen T cell responses.…”

ICER/CREM‐mediated transcriptional attenuation of IL‐2 and its role in suppression by regulatory T cells

“…Furthermore, CTLA-4 increases T cell motility and overrides TCR induced stop signals required for stable conjugate formation between T cells and antigen presenting cells (APC) [7]. Critical importance of cAMP/protein kinase A (PKA) pathway for regulation of immune tolerance [8] is further supported by inability to develop T and B lymphocytes in mice conditionally deficient in PKA-RIa subunit (Dr. Hua Gu, Columbia University, personal communication).…”