T-FINDER: A highly sensitive, pan-HLA platform for functional T cell receptor and ligand discovery.

Effective, unbiased, high-throughput methods to functionally identify both class II and class I HLA-presented T cell epitopes and their cognate T cell receptors (TCRs) are essential for and prerequisite to diagnostic and therapeutic applications, yet remain underdeveloped. Here, we present T-FINDER [T cell Functional Identification and (Neo)-antigen Discovery of Epitopes and Receptors], a system to rapidly deconvolute CD4 and CD8 TCRs and targets physiologically processed and presented by an individual's unmanipulated, complete human leukocyte antigen (HLA) haplotype. Combining a highly sensitive TCR signaling reporter with an antigen processing system to overcome previously undescribed limitations to target expression, T-FINDER both robustly identifies unknown peptide:HLA ligands from antigen libraries and rapidly screens and functionally validates the specificity of large TCR libraries against known or predicted targets. To demonstrate its capabilities, we apply the platform to multiple TCR-based applications, including diffuse midline glioma, celiac disease, and rheumatoid arthritis, providing unique biological insights and showcasing T-FINDER's potency and versatility.

A conserved Bacteroidetes antigen induces anti-inflammatory intestinal T lymphocytes.

The microbiome contributes to the development and maturation of the immune system. In response to commensal bacteria, intestinal CD4+ T lymphocytes differentiate into functional subtypes with regulatory or effector functions. The development of small intestine intraepithelial lymphocytes that coexpress CD4 and CD8αα homodimers (CD4IELs) depends on the microbiota. However, the identity of the microbial antigens recognized by CD4+ T cells that can differentiate into CD4IELs remains unknown. We identified ß-hexosaminidase, a conserved enzyme across commensals of the Bacteroidetes phylum, as a driver of CD4IEL differentiation. In a mouse model of colitis, ß-hexosaminidase-specific lymphocytes protected against intestinal inflammation. Thus, T cells of a single specificity can recognize a variety of abundant commensals and elicit a regulatory immune response at the intestinal mucosa.

Does this patient have Parkinson disease?

CONTEXT: Diagnosis of Parkinson disease (PD) remains challenging. An accurate diagnosis is important because effective symptomatic treatment for PD is available. OBJECTIVE: To systematically review the literature for information on the precision and accuracy of the clinical examination for diagnosing PD. DATA SOURCES: MEDLINE database was searched for all English-language articles related to the diagnosis of PD published from January 1966 through April 2001. The reference lists of all articles retrieved were searched for additional relevant sources. STUDY SELECTION: Studies in which patients presented with 1 or more typical features of PD were included if the final diagnosis was confirmed by a suitable criterion standard and data could be extracted to determine the accuracy of 1 or more symptoms or signs. Variability in descriptions of symptoms and signs made it impossible to combine data across existing studies for most findings. DATA SYNTHESIS: We identified 6 studies that met our criteria. The positive (presence) likelihood ratios (LRs) for tremor as a symptom of PD ranged from 1.3 to 17 (range of negative [absence] LRs, 0.24 to 0.60). Tremor as a sign of PD produced a range of positive LRs from 1.3 to 1.5 (negative LRs, 0.47 to 0.61). Clinical features useful in the diagnosis of PD include a history of the combination of symptoms of rigidity and bradykinesia (positive LR, 4.5; negative LR, 0.12); a history of loss of balance (range of positive LRs, 1.6 to 6.6; range of negative LRs, 0.29 to 0.35), symptoms of micrographia (range of positive LRs, 2.8 to 5.9; range of negative LRs, 0.30 to 0.44), and a history of shuffling gait (range of positive LRs, 3.3 to 15; range of negative LRs, 0.32 to 0.50). Trouble with certain tasks such as turning in bed (positive LR, 13; negative LR, 0.56), opening jars (positive LR, 6.1; negative LR, 0.26), and rising from a chair (range of positive LRs, 1.9 to 5.2; range of negative LRs, 0.39 to 0.58). Useful signs include the glabella tap test (positive LR, 4.5; negative LR, 0.13), difficulty walking heel-to-toe (positive LR, 2.9; negative LR, 0.32), and rigidity (range of positive LRs, 0.53 to 2.8; range of negative LRs, 0.38 to 1.6). Significant selection bias was detected in all studies included for review. CONCLUSIONS: Symptoms of tremor, rigidity, bradykinesia, micrographia, shuffling gait, and difficulty with the tasks of turning in bed, opening jars, and rising from a chair should be carefully reviewed in all patients with suspected PD. The glabella tap and heel-to-toe tests also should be assessed.