B7-CD28 Interaction Promotes Proliferation and Survival but Suppresses Differentiation of CD4−CD8− T Cells in the Thymus

Zheng, Xincheng; Gao, Jianxin; Chang, Xing; Wang, Yin; Liu, Yan; Wen, Jing; Zhang, Huiming; Zhang, Jian; Liu, Yang; Zheng, Pan

doi:10.4049/jimmunol.173.4.2253

Cited by 18 publications

(22 citation statements)

References 51 publications

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“…The 2 molecules can cooperate to regulate early stages of T-lineage lymphocyte development in the thymus. 47 Therefore, it will be important to extend these studies with compound KO mice.…”

Section: Discussionmentioning

confidence: 99%

CD86 is expressed on murine hematopoietic stem cells and denotes lymphopoietic potential

Shimazu

Iida

Zhang

et al. 2012

Blood

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IntroductionA large body of information exists about molecular mechanisms involved in maintaining HSC integrity, and many studies have identified unique markers associated with differentiation. 1 However, several of these parameters differ between strains of mice or change dramatically according to developmental age, activation status, or inflammation. [2][3][4] This issue gained importance with the realization that HSCs are normally heterogeneous and that functionally distinct subsets can be resolved according to phenotypes. [5][6][7][8] As one example, we discovered that a unique population of lineage marker Ϫ Sca-1 ϩ c-Kit ϩ (LSK) CD150 ϩ CD48 Ϫ HSCs lacked CD86. 9 CD86 Ϫ HSCs accumulated in old mice as well as young mice repeatedly injected with lipopolysaccharide (LPS). At least some HSCs in those animals had low ability to self-renew and restore the adaptive immune system when transplanted. In addition, HSCs in the chronically stimulated animals were abnormally in cycle. 9 However, the relation between those phenomena and CD86 loss was unclear.B7-1 (CD80) and B7-2 (CD86) are type I transmembrane proteins that were originally identified as ligands for CD28/CTLA-4. 10 Murine CD80 and CD86 share ϳ 28% amino acid identity, but both are capable of using conserved binding sites to recognize either human or mouse CD28. Although this is important for T-cell activation, another ligand, CTLA-4 functions as an inhibitory receptor for immune responses. 11 CD86 is constitutively expressed on dendritic cells, B cells, and thymic epithelial cells. CD80 is only expressed by activated B and T cells. Several reports suggest that CD80 and CD86 have overlapping functions because double knockout (KO) mice have more severe defects in immune responses than single KOs. 12 However, one report suggests there are differential functions. 13 Given the importance of CD80/86 for T-cell activation, blocking Abs are valuable in establishing tolerance during BM transplantation. 14 Marrow stromal cells express the CD28 ligand in close proximity to B-lineage progenitors, and CD28 might slightly enhance B lymphopoiesis. 15 CD86 is expressed by many HSCs, 7,9 but gain or loss relative to hematopoiesis has not been explored. We now report that CD86 loss on stem and progenitor cells closely parallels their loss of lymphopoietic potential. It is a uniquely useful marker for appreciating functional heterogeneity among HSCs that are otherwise similar. MethodsMice C57BL/6 (CD45.2 alloantigen), CD86-deficient (CD86 Ϫ/Ϫ ), and B6-SJL/ Ly5.1 (CD45.1 alloantigen) mice were purchased from The Jackson Laboratory. C57BL/6 ϫ SJL/Ly5.1 F 1 (CD45.1 and CD45.2 alloantigens) and RAG1/GFP (recombinase activator gene 1/green fluorescent protein) knock-in mice were bred and maintained in the Laboratory Animal Resource Center at the Oklahoma Medical Research Foundation. PU.1 fl/fl and C/EBP␣ fl/fl mice were bred with Mx1 Cre mice to generate PU.1 fl/fl or C/EBP␣ fl/fl ϪMx1 Cre mice. Those and C/EBP␤KO mice were bred and maintained in Beth Israel Deaconess Medical C...

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“…The 2 molecules can cooperate to regulate early stages of T-lineage lymphocyte development in the thymus. 47 Therefore, it will be important to extend these studies with compound KO mice.…”

Section: Discussionmentioning

confidence: 99%

CD86 is expressed on murine hematopoietic stem cells and denotes lymphopoietic potential

Shimazu

Iida

Zhang

et al. 2012

Blood

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“…CD28 is more highly expressed in DN4 cells than DN3, and CD28 Ϫ/Ϫ DN thymocytes have impaired proliferation of DN4 cells (19). Based on these data, we tested whether Gads might regulate CD28 expression.…”

Section: Gads Regulates Cytokine Receptor Expressionmentioning

confidence: 99%

Gads−/− Mice Reveal Functionally Distinct Subsets of TCRβ+ CD4−CD8− Double-Negative Thymocytes

Zeng

Dalheimer

Yankee

2007

The Journal of Immunology

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TCRβ expression in CD4−CD8− double-negative (DN) thymocytes induces signaling pathways that promote survival and proliferation, as well as differentiation into CD4+CD8+ double-positive thymocytes. The signaling pathways that regulate survival, proliferation, and differentiation remain unclear. We used Gads-deficient mice to investigate the signaling pathways that regulate these cell fates. During this investigation, we focused on TCRβ+ DN thymocytes and found that there are at least three functionally distinct subsets of TCRβ+ DN thymocytes: TCRβ+ DN3E, TCRβ+ DN3L, and TCRβ+ DN4. Survival and proliferation of TCRβ+ DN3E were independent of Gads, but survival and proliferation of TCRβ+ DN3L cells were Gads dependent. Likewise, expression of Bcl-2 in TCRβ+ DN3E cells was Gads independent, but Gads was necessary for Bcl-2 expression in TCRβ+ DN3L cells. Bcl-2 expression was not dependent on Gads in TCRβ+ DN4 cells, but proliferation of TCRβ+ DN4 cells was Gads dependent. Gads was not required for the differentiation of DN thymocytes into DP thymocytes. In fact, Gads−/− DN3E cells differentiated into DP thymocytes more readily than wild-type cells. We conclude that signaling pathways required to initiate TCRβ-induced survival and proliferation are distinct from the pathways that maintain survival and proliferation. Furthermore, signaling pathways that promote survival and proliferation may slow differentiation.

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“…This has made studying the effect of CD28 costimulation on memory CD8 ϩ T cell response upon rechallenge using CD28-deficient mice impossible. Additionally, although CD28-deficient mice have normal numbers of B and T cell populations (23), one cannot exclude that given the importance of CD28 costimulation in thymic T cell development (27)(28)(29) lack of CD28 during T cell development could lead to defective mature T cells, which complicates studying memory responses in these mice.…”

mentioning

confidence: 99%

Memory CD8+ T Cells Require CD28 Costimulation

Borowski

Boesteanu

Mueller

et al. 2007

The Journal of Immunology

127

147

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CD8+ T cells are a critical component of the adaptive immune response against infections and tumors. A current paradigm in immunology is that naive CD8+ T cells require CD28 costimulation, whereas memory CD8+ T cells do not. We show here, however, that during viral infections of mice, costimulation is required in vivo for the reactivation of memory CD8+ T cells. In the absence of CD28 costimulation, secondary CD8+ T cell responses are greatly reduced and this impairs viral clearance. The failure of CD8+ T cells to expand in the absence of CD28 costimulation is CD4+ T cell help independent and is accompanied by a failure to down-regulate Bcl-2 and by cell cycle arrest. This requirement for CD28 costimulation was shown in both influenza A and HSV infections. Thus, contrary to current dogma, memory CD8+ T cells require CD28 costimulation to generate maximal secondary responses against pathogens. Importantly, this CD28 requirement was shown in the context of real infections were multiple other cytokines and costimulators may be up-regulated. Our findings have important implications for pathogens, such as HIV and measles virus, and tumors that evade the immune response by failing to provide CD28 costimulation. These findings also raise questions about the efficacy of CD8+ T cell-based vaccines against such pathogens and tumors.

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B7-CD28 Interaction Promotes Proliferation and Survival but Suppresses Differentiation of CD4−CD8− T Cells in the Thymus

Cited by 18 publications

References 51 publications

CD86 is expressed on murine hematopoietic stem cells and denotes lymphopoietic potential

CD86 is expressed on murine hematopoietic stem cells and denotes lymphopoietic potential

Gads−/− Mice Reveal Functionally Distinct Subsets of TCRβ+ CD4−CD8− Double-Negative Thymocytes

Memory CD8+ T Cells Require CD28 Costimulation

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