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Intraepithelial T cells: Specialized T cells at epithelial surfaces
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
Substantial efforts have been brought to bear on understanding the origin of IETs, with special emphasis on the CD8αα+ nIETs, in part due to their unusual phenotype, and on TCRαβ nIETs, for their restricted TCR repertoire highly enriched for self-reactive TCRs. Moreover, the intestine has been described as a primary lymphoid organ based on the demonstration that certain lymphocytes are present in the intestinal epithelium of neonatal-thymectomized mice and that IETs are present in primitive vertebrates. This concept appears reasonable considering that gut-associated lymphoid tissue arose prior to the thymus and may be the evolutionary antecedent. Nevertheless, in the absence of a functional thymus, as in nude mice, IETs are drastically reduced, and the residual lymphocytes chiefly express TCRγδ. Additionally, extrathymic development in the absence of irradiation results mainly in TCRγδ nIETs, suggesting that radiation promotes extrathymic T-cell development. Neonatal or fetal thymus grafting studies have demonstrated that all IETs are thymus derived, and consistent with this, neonatal thymectomy largely ablates all IET populations. These findings indicate that under normal circumstances, IETs are thymus derived but that, similar to the iIETs, further maturation may occur in the intestine. Lymphoid structures at the base of some small intestinal crypts in the mouse, termed cryptopatches, contain hematopoietic c-Kit+, interleukin-7 receptor α (IL-7Rα+), Thy1+, CD44+, Lin− precursors, and were proposed as a potential site where such “extrathymic” development could occur, although cryptopatches have not been described in humans or other species. The formation of mouse cryptopatches is interleukin-7 (IL-7) and IL-15 dependent and enterocyte-restricted IL-7 is crucial for cryptopatches and sufficient for extrathymic development of TCRγδ T cells. Cryptopatches, however, are not absolutely required for TCRγδ nIETs. Moreover, athymic RAG reporter mice show RAG expression in mesenteric lymph nodes (MLNs) and PP, but not in cryptopatches or IETs. Nevertheless, MLN and PP are also not required for extrathymic IETs, and RAG expression in mucosal tissues is negligible in euthymic animals, suggesting that the extrathymic pathway is a secondary consequence of a lack of thymus and thymus-derived cells and signals.
Advances in the genetics of acute lymphoblastic leukemia in adults and the potential clinical implications
Published in Expert Review of Hematology, 2018
Netanel A. Horowitz, Doaa Akasha, Jacob M. Rowe
Approximately 50% of patients with Ph-like ALL have overexpression of cytokine receptor-like factor 2 (CRLF2) [24]. CRFL2 pairs with interleukin-7 receptor α to form a heterodimeric thymic stromal lymphopoietin receptor implicated in early B cell development [26]. This gene is located on the pseudo-autosomal region 1(PAR1) of chromosomes Xp22/Yp11 [27]. The most common genetic alterations involving the CRFL2 gene are deletion of PAR1 which joins CRFL2 to P2RY8 gene resulting in a new CRFL2-P2RY8 transcript [28], and a translocation which joins CRFL2 to the immunoglobulin heavy chain gene IGH located on chromosome 14q32 [29]. Fusion of CLFR2 to another PAR1 gene, CSF2RA has also been described [30]. Among ALL patients harboring CFLR2 alterations, almost half have concomitant activating JAK1 or JAK2 mutations [31]. CRFL2 overexpression and JAK2 mutations collaborate and lead to constitutive activation of the JAK-STAT signalling [31]. Genetic abnormalities in the JAK2 protein without concomitant CFLR2 aberrations have been described in young adults with the Ph-like phenotype [32]. The JAK-STAT signaling pathway may also be activated by rearrangement of the erythropoietin receptor (EPOR-R) gene with other genes (IGH, IGK LAIR1 and THAD) which results in overexpression of EPOR-R that have lost negative regulatory domains. These cases have been demonstrated in about 1% of ALL patients [32].
Merits and complexities of modeling multiple sclerosis in non-human primates: implications for drug discovery
Published in Expert Opinion on Drug Discovery, 2018
Bert A. ‘t Hart, Jon D. Laman, Yolanda S. Kap
In conclusion, this new model implies a considerable improvement at 3 of the 4 R criteria. Nevertheless, unforeseen complications emerged when the model was used in preclinical trials. We will discuss a well-designed and sufficiently powered (7 twins) efficacy study testing a novel mAb against the interleukin-7 receptor α-chain (CD127) [68]. The observation that certain polymorphisms in the gene encoding the interleukin-7 receptor α-chain (CD127) are associated with enhanced risk to develop MS indicates potential relevance of the mAb as treatment for MS [69,70]. Unexpectedly, we observed a dichotomous response of the model to the therapeutic anti-CD127 mAb, as the mAb was effective in 3 twins with short time interval to clinically evident EAE (<70 days) fast responders), while it was ineffective in 3 twins with a late EAE onset (>105 days; slow progressors). This dichotomous response and the fact that one twin failed to develop clinical EAE killed the statistical evaluation of our well-designed experiment that was powered on a 100% response-to-treatment. In a subsequent study in which the effect of targeted dietary intervention on EAE susceptibility in marmosets was tested, a similar heterogeneous response was detected (Kap et al.; manuscript submitted 2017). At this moment, we have no other explanation for the variation in the response to immunization and in the response to treatment than the genetic diversity of this outbred model. It is important to emphasize here that in the clinical trials of currently registered drugs, such as interferon-β for RRMS, a variable response to treatment had been observed as well [9].