Citations

Quantitative activity through the TCR-proximal protein network specifies thymic positive versus negative selection.

Abstract CD8 T cells must integrate antigenic and inflammatory signals to differentiate into efficient effector and memory T cells able to protect us from infections. The mechanisms by which TCR signaling and proinflammatory cytokine receptor signaling cooperate in these processes are poorly defined. In this study, we show that IL-12 and other proinflammatory cytokines transduce signals through the TCR signalosome in a manner that requires Fyn activity and self-peptide–MHC (self-pMHC) interactions. This mechanism is crucial for CD8 innate T cell functions. Loss of Fyn activity or blockade of self-pMHC interactions severely impaired CD8 T cell IFN-γ and NKG2D expression, proliferation, and cytotoxicity upon cytokine-mediated bystander activation. Most importantly, in the absence of self-pMHC interactions, CD8 memory T cells fail to undergo bystander activation upon an unrelated infection. Thus, CD8 T cell bystander activation, although independent of cognate Ag, still requires self-pMHC and TCR signaling.

Abstract TCR engagement by peptide-MHC class I (pMHC) ligands induces a conformational change (Δc) in CD3 (CD3Δc) that contributes to T cell signaling. We found that when this interaction took place between primary T lineage cells and APCs, the CD8 coreceptor was required to generate CD3Δc. Interestingly, neither enhancement of Ag binding strength nor Src kinase signaling explained this coreceptor activity. Furthermore, Ag-induced CD3Δc was developmentally attenuated by the increase in sialylation that accompanies T cell maturation and limits CD8 activity. Thus, both weak and strong ligands induced CD3Δc in preselection thymocytes, but only strong ligands were effective in mature T cells. We propose that CD8 participation in the TCR/pMHC interaction can physically regulate CD3Δc induction by “translating” productive Ag encounter from the TCR to the CD3 complex. This suggests one mechanism by which the developmentally regulated variation in CD8 sialylation may contribute to the developmental tuning of T cell sensitivity.

The General Well-being Schedule is a brief indicator of subjective feelings of psychological well-being and distress. It is easy to administer, reliable, and valid, although its validity with American Indians has not been established. This study then assessed reliability, validity, and factor structure for a sample of 88 diabetic American Indians, who sought care for diabetes at an Indian Health Service hospital. Cronbach alpha was .89. A factor analysis indicated four dimensions. Adequate concurrent and divergent validity were noted in association with scores on the Beck Depression Inventory-Second Edition, the depression scale on the Symptom Checklist-90-Revised, and Family-Adaptation, Partnership, Growth, Affection, & Resolve. These results suggest that the General Well-being Schedule is a reliable and valid measure of general well-being for this population of American Indians.

According to the Indian Health Service, substance abuse and Type 2 diabetes are serious problems among Native Americans. To assess substance use in a medical setting, valid screening tests are needed so the Alcohol Use Disorders Identification Test (AUDIT), a simple brief screen for excessive drinking, and the CAGE-adapted to Include Drugs (CAGE-AID) for identifying primary care patients with alcohol and drug disorders were given 50 Northern Plains American Indians with diabetes. Both are short, easy to administer, have good sensitivity and specificity, and can be easily incorporated into a medical history protocol or intake procedure. Reliability coefficients were above .90 and appeared to have sufficient concurrent and divergent validity indicated by moderate correlations with the General Well-being Schedule ( rs = –.39 and –.36), the Family-Adaptation, Partnership, Growth, Affection, & Resolve ( r = –.47 and –.36), and the Beck Depression Inventory-II ( r = .36 and .29).

Following infection, naïve CD8 + T cells bearing pathogen-specific T cell receptors (TCRs) differentiate into a mixed population of short-lived effector and long-lived memory T cells to mediate an adaptive immune response. How the TCR regulates memory T cell development has remained elusive. Using a mutant TCR transgenic model, we found that point mutations in the TCR β transmembrane domain (βTMD) impair the development and function of CD8 + memory T cells without affecting primary effector T cell responses. Mutant T cells are deficient in polarizing the TCR and in organizing the nuclear factor κB signal at the immunological synapse. Thus, effector and memory states of CD8 + T cells are separable fates, determined by differential TCR signaling.