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.

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.

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.

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.

Among the compared modalities, ultrasonography was superior for detecting lymph node metastases, and PET-CT was superior for the detection of distant metastases in both the staging and surveillance of melanoma patients.

Regulatory T (Treg) cells express tumor necrosis factor receptor superfamily (TNFRSF) members, but their role in thymic Treg development is undefined. We demonstrate that Treg progenitors highly express the TNFRSF members GITR, OX40, and TNFR2. Expression of these receptors correlates directly with T cell receptor (TCR) signal strength, and requires CD28 and the kinase TAK1. Neutralizing TNFSF ligands markedly reduced Treg development. Conversely, TNFRSF agonists enhanced Treg differentiation by augmenting IL-2R/STAT5 responsiveness. GITR-ligand costimulation elicited a dose-dependent enrichment of lower-affinity cells within the Treg repertoire. In vivo, combined inhibition of GITR, OX40 and TNFR2 abrogated Treg development. Thus TNFRSF expression on Treg progenitors translates strong TCR signals into molecular parameters that specifically promote Treg differentiation and shape the Treg repertoire.

Thymic positive and negative selection events generate a T-cell repertoire that is MHC restricted and self-tolerant. The number of T cells undergoing positive and negative selection in normal mice has never been firmly established. We generated mice that lack the proapoptotic molecule Bim (bcl2l11) together with a Nur77 GFP transgene, which allowed the identification and enumeration of T cells that would normally undergo clonal deletion. Using this method, we report the striking observation that six times more cells undergo negative selection than complete positive selection. Seventy-five percent of the negatively selected cells are deleted at the double positive stage in the thymic cortex, compared with 25% at the single positive stage in the medulla. The fact that more thymocytes are highly reactive to MHC than are weakly reactive is inconsistent with a random model of recognition and suggests that T-cell recognition is MHC biased. Furthermore, Bim −/− mice had an increased number of GFP hi cells in the peripheral lymphoid tissue and a corresponding increase in antigen experienced or anergic cell phenotype. Our data also show that the CD4+ T cells that are clonally deleted experienced only slightly stronger T-cell receptor signaling than those that developed into regulatory T cells.lymphocyte development | thymus P ositive and negative selection events in the thymus create a T-cell repertoire that is both major histocompatibility complex (MHC) restricted and self-tolerant. It is well established that the affinity of the T-cell receptor (TCR) for self-MHC ligands is critical in determining these fates. Low-affinity interactions promote survival and maturation, whereas high-affinity interactions promote deletion, with a surprisingly narrow threshold distinguishing these two (1). Nonetheless, it is unclear how many T-cell clones achieve this threshold and become deleted relative to the number that are positively selected. Because the T-cell receptor is formed by somatic recombination with nontemplated nucleotide addition, the amino acids in the antigen binding region are highly diverse and essentially random. Thus, it has been assumed that the number of clones that can interact with any given peptide MHC complex with high affinity (negative selection) would be smaller than the number of clones that could interact more weakly (positive selection). However, attempts to understand what fraction of the repertoire undergoes positive and negative selection have led to disparate findings.The murine thymus exports ∼1-4 × 10 6 cells per day, and these are predominantly naïve CD4 and CD8 T cells (2). Thus, based on the previous estimates of negative selection, one might predict that the number of self-reactive clones generated and deleted per day would be much smaller than this number. However, because apoptotic cells are so efficiently engulfed by thymic macrophages, it has been challenging to quantify clonal deletion. Consequently, the frequency with which clonal deletion occurs relative to positive selection has been co...