CD28 expression redefines thymocyte development during the pre-T to DP transition

Teague, T. Kent; Tan, Chibing; Marino, Julie H.; Davis, Brenda K.; Taylor, Ashlee; Huey, Ryan; Wiele, C. Justin Van De

doi:10.1093/intimm/dxq020

Cited by 34 publications

(42 citation statements)

References 26 publications

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“…CD4 − CD8 − double-negative (DN) thymocytes, which precede the maturation to DP, can be further divided into various populations according to their differential expression of the CD44, CD25, and CD28 surface markers. 20 In particular, the CD44 − CD25+CD28+ (DN3b) fraction represents thymocytes that have undergone β-selection upon successful rearrangement of their TCR-β locus. They will subsequently progress to DN3c, DN4a, and DN4b, and ultimately to DP as depicted in Figure 4a.…”

Section: Resultsmentioning

confidence: 99%

PAXX and Xlf interplay revealed by impaired CNS development and immunodeficiency of double KO mice

et al. 2017

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The repair of DNA double-stranded breaks (DNAdsb) through non-homologous end joining (NHEJ) is a prerequisite for the proper development of the central nervous system and the adaptive immune system. Yet, mice with Xlf or PAXX loss of function are viable and present with very mild immune phenotypes, although their lymphoid cells are sensitive to ionizing radiation attesting for the role of these factors in NHEJ. In contrast, we show here that mice defective for both Xlf and PAXX are embryonically lethal owing to a massive apoptosis of post-mitotic neurons, a situation reminiscent to XRCC4 or DNA Ligase IV KO conditions. The development of the adaptive immune system in Xlf − / − PAXX −/− E18.5 embryos is severely affected with the block of B-and T-cell maturation at the stage of IgH and TCRβ gene rearrangements, respectively. This damaging phenotype highlights the functional nexus between Xlf and PAXX, which is critical for the completion of NHEJ-dependent mechanisms during mouse development. Cell Death and Differentiation (2018) 25, 444-452; doi:10.1038/cdd.2017; published online 27 October 2017All living organisms are subjected to multitude sources of DNA damage during their lifespan, either as a result of external assault or endogenous physiological processes.1 Among endogenous sources of physiological DNAdsb is the somatic rearrangement of immunoglobulin (Ig) and TCR genes in B and T lymphocytes, respectively, during the diversification of the adaptive immune system through V(D)J recombination.2 DNA double-stranded breaks (DNAdsb) are considered the most toxic lesions. DNAdsbs are repaired by two main mechanisms: the homologous recombination (HR) in cycling cells, when a sister chromatid is available as DNA repair template, and the non-homologous end joining (NHEJ) during all phases of the cell cycle.NHEJ proceeds via the simple religation of DNA ends without the need for a repair template.3 Briefly, the NHEJ is composed of seven core factors comprising the Ku70/80/ DNA-PKcs (DNA-dependent protein kinase catalytic subunit) complex, which recognizes and protects the broken DNA ends, the Artemis endo/exonuclease, which participates, when needed, in processing the DNA ends and the XRCC4/ DNA-Ligase IV/Xlf complex, which ultimately reseals the DNA break. The critical function of the NHEJ apparatus in various aspects of higher eukaryote development has been extensively perceived in several animal and human pathological conditions. As emblematic examples, loss of function of either XRCC4 or DNA ligase IV results in embryonic lethality in mice 4,5 and mutations in Artemis or DNA-PKcs result in severe combined immunodeficiency conditions in both men and mice, owing to aborted V(D)J recombination. 6 In addition, defects in NHEJ results in genetic instability and the propensity to develop various types of cancers, notably leukemia and lymphomas. Recently, a new DNA repair factor, PAXX (PAralog of XRCC4 and Xlf, also known as C9orf142 or XLS), has been identified independently by three laboratories based on bioinformatic...

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Section: Resultsmentioning

confidence: 99%

PAXX and Xlf interplay revealed by impaired CNS development and immunodeficiency of double KO mice

et al. 2017

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“…Pre-β-selection DN3a thymocytes (7AAD − CD25 + CD44 − Lin − CD28 − ) were sorted as previously described (40,41), stained with Celltrace Violet, and co-cultured with OP9-DL1 cells. After 4 days in culture, DN3a cells from wild-type mice developed into DP cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

Yin Yang 1 Promotes Thymocyte Survival by Downregulating p53

Chen

Foreman

Sant’Angelo

et al. 2016

The Journal of Immunology

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Yin Yang 1 (YY1) is a zinc finger protein that functions as a transcriptional activator or repressor and participates in multiple biological processes, including development and tumorigenesis. To investigate the role of YY1 in developing T cells, we used mouse models that depleted YY1 at two distinct stages of thymocyte development. When YY1 was depleted in CD4−CD8− double negative (DN) thymocytes, development to the CD4+CD8+ double positive (DP) stage was impaired, due to increased apoptosis that prevented expansion of post–β-selection thymocytes. When YY1 was depleted in DP thymocytes, they underwent increased cell-autonomous apoptosis in vitro and displayed a shorter lifespan in vivo, as judged by their ability to undergo secondary Vα-to-Jα recombination. Mechanistically, we found that the increased apoptosis in YY1-deficient thymocytes was attributed to overexpression of p53, because concurrent loss of p53 completely rescued the developmental defects of YY1-deficient thymocytes. These results indicated that YY1 functions as a critical regulator of thymocyte survival and that it does so by suppressing the expression of p53.

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“…We used the EVA1-deficient mice (B6.Eva1 ko/ko ) as negative control to show the specificity of the G9P3-1 Mab to detect EVA1 expression on DN3 cells. Extended comparative analysis between two development-relevant DN3 subsets (27) DN3a (CD25 + CD44 low CD28 low ) and DN3b (CD25 + CD44 low CD28 high ) showed no significant differences in EVA1 protein expression, indicating that EVA1 is homogeneously, specifically, and highly expressed at the DN3 development stage.…”

Section: Establishment and Reactivity Of Hybridoma Cell Linesmentioning

confidence: 90%

A Monoclonal Antibody Against the Extracellular Domain of Mouse and Human Epithelial V-like Antigen 1 Reveals a Restricted Expression Pattern Among CD4- CD8- Thymocytes

Garabatos

Blanco

Fandos

et al. 2014

Monoclonal Antibodies in Immunodiagnosis and Immunotherapy

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Expression of transcripts for the homotypic adhesion protein epithelial V-like antigen 1 (EVA1), also known as myelin protein zero like-2 (Mpzl2), is known to be present in thymic stromal cells. However, protein expression within different thymic subsets, stromal and/or lymphoid, has not been characterized due a lack of specific reagents. To address this, we generated a hybridoma (G9P3-1) secreting a monoclonal antibody (G9P3-1Mab), reactive against both human and mouse EVA1. The G9P3-1Mab was generated by immunizing Mpzl2-deficient gene-targeted mice with the extracellular domain of EVA1, followed by a conventional hybridoma fusion protocol, illustrating the feasibility of using gene-targeted mice to generate monoclonal antibodies with multiple species cross-reactivity. We confirmed expression of EVA1 on cortical and medullary epithelial cell subsets and revealed a restricted pattern of expression on CD4- CD8- double negative (DN) cell subsets, with the highest level of expression on DN3 (CD44(low)CD25(+)) thymocytes. G9P3-1MAb is a valuable reagent to study thymic T cell development and is likely useful for the analysis of pathological conditions affecting thymopoiesis, such as thymic involution caused by stress or aging.

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CD28 expression redefines thymocyte development during the pre-T to DP transition

Cited by 34 publications

References 26 publications

PAXX and Xlf interplay revealed by impaired CNS development and immunodeficiency of double KO mice

PAXX and Xlf interplay revealed by impaired CNS development and immunodeficiency of double KO mice

Yin Yang 1 Promotes Thymocyte Survival by Downregulating p53

A Monoclonal Antibody Against the Extracellular Domain of Mouse and Human Epithelial V-like Antigen 1 Reveals a Restricted Expression Pattern Among CD4- CD8- Thymocytes

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