Generation of a Nur77 reporter mouse is used to demonstrate TCR signal strength during thymic selection and peripheral maintenance of conventional and nonconventional T cell subsets and presents a novel tool for studying antigen receptor activation in vivo.

Purpose We evaluated clinical features and survival outcomes among patients with signet ring and mucinous histologies of colorectal adenocarcinoma using data from the National Cancer Data Base (NCDB). Methods Patients aged 18–90 years with colorectal adenocarcinoma diagnosed between 1998 and 2002 were identified from the NCDB. Site-stratified (colon vs rectum) survival analysis was performed using multivariate relative survival adjusted for multiple clinicopathologic and treatment variables. Results The study included 244,794 patients: 25,546 (10%) with mucinous, 2,260 (1%) with signet ring, and 216,988 (89%) with nonmucinous, non–signet ring adenocarcinoma. Mucinous and signet ring cancers were more frequently right-sided (60% and 62%, respectively) than were nonmucinous, non–signet ring adenocarcinomas (42%, P < .001). Signet ring histology was associated with a higher stage (P < .001), and 77.2% of signet ring tumors were high-grade lesions, compared with 20% of mucinous and 17% of non–signet ring, nonmucinous adenocarcinomas (P < .001). After adjustment for covariates, signet ring histology was independently associated with higher risk of death (HR 1.42, 95% confidence interval [CI] 1.33-1.51, and HR 1.57, CI 1.38-1.77, for tumors located in the colon and rectum, respectively). Mucinous tumors of the rectum (HR 1.22, CI 1.16-1.29), but not the colon (HR 1.03, CI 1.00-1.06), were associated with increased risk of death. Conclusion Signet ring cell adenocarcinomas of the colon and rectum and mucinous adenocarcinomas of the rectum are associated with poorer survival. These aggressive histologic variants of colorectal adenocarcinoma should be targeted for research initiatives to improve outcomes.

Somatic recombination of TCR genes in immature thymocytes results in some cells with useful TCR specificities, but also many with useless or potentially self-reactive specificities. Thus thymic selection mechanisms operate to shaper the T cell repertoire. Thymocytes that have a TCR with low affinity for self-peptide-MHC complexes are positively selected to further differentiate and function in adaptive immunity, whereas useless ones die by neglect. Clonal deletion and clonal diversion (Treg differentiation) are the major processes in the thymus that eliminate or control self-reactive T cells. Although these processes are thought to be efficient they are insufficient to in all circumstances. Thus, peripheral tolerance processes exists, wherein self-reactive T cells become functional unresponsive (anergy) or are deleted after encountering self-antigens outside of the thymus. Recent advances in mechanistic studies of central and peripheral T cell tolerance are promoting the development of therapeutic strategies to treat autoimmune disease and cancer and improve transplantation outcome.

Melanoma is a public health concern for all ethnic populations. Differences in disease stage at presentation contributes to disparities in survival. Understanding melanoma in minority populations may lead to early detection and ultimately save lives.

The strength of self-peptide–major histocompatibility complex (MHC) recognition dictates naïve CD8+ T cell homeostasis, but its effect on foreign antigen reactivity is controversial. As CD5 expression correlates with self-recognition, we studied CD5lo and CD5hi naïve CD8+ T cells. Gene expression characteristics suggested CD5hi cells were better poised for reactivity and differentiation compared to the CD5lo population, and we found that the CD5hi pool exhibited more efficient clonal recruitment and expansion, as well as enhanced reactivity to inflammatory cues, during recognition of foreign antigen. Yet foreign peptide–MHC recognition was similar for both subsets. Thus, CD8+ T cells with higher self-reactivity dominate the immune response against foreign antigens, with implications for T cell repertoire diversity and autoimmunity.