A potential role for CD69 in thymocyte emigration

Feng, Chiguang; Woodside, Kenneth J.; Vance, Barbara A.; El-Khoury, Dalal; Cañelles, Matilde; Lee, Jan; Gress, Ronald E.; Fowlkes, B. J.; Shores, Elizabeth W.; Love, Paul E.

doi:10.1093/intimm/dxf020

Cited by 133 publications

(121 citation statements)

References 35 publications

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“…CD69 is an antagonist of S1PR1, blocking the S1P‐mediated egress of lymphocytes from secondary lymphoid organs into the blood 140, 141, 142. It is remarkable that in CD69 + memory T cells of bone marrow, S1PR1 expression is blocked on the level of transcription, since it has also been reported that CD69 can directly block surface expression of S1PR1 143.…”

Section: The Lifestyle Of Bone Marrow Memory T Lymphocytesmentioning

confidence: 99%

Immunological memories of the bone marrow

Chang

Tokoyoda

Radbruch

2018

Immunological Reviews

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SummaryMemory for antigens once encountered is a hallmark of the immune system of vertebrates, providing us with an immunity adapted to pathogens of our environment. Despite its fundamental relevance, the cells and genes representing immunological memory are still poorly understood. Here we discuss the concept of a circulating, proliferating, and ubiquitous population of effector lymphocytes vs concepts of resting and dormant populations of dedicated memory lymphocytes, distinct from effector lymphocytes and residing in defined tissues, particularly in barrier tissues and in the bone marrow. The lifestyle of memory plasma cells of the bone marrow may serve as a paradigm, showing that persistence of memory lymphocytes is not defined by intrinsic “half‐lives”, but rather conditional on distinct survival signals provided by dedicated niches. These niches are organized by individual mesenchymal stromal cells. They define the capacity of immunological memory and regulate its homeostasis.

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Section: The Lifestyle Of Bone Marrow Memory T Lymphocytesmentioning

confidence: 99%

Immunological memories of the bone marrow

Chang

Tokoyoda

Radbruch

2018

Immunological Reviews

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“…Another agonist-independent mechanism for modulation of S1P 1 receptor surface expression is the observed direct interaction of S1P 1 with CD69, which prevents cell surface expression of both molecules when co-expressed (41). Transgenic expression of CD69 in T cells led to accumulation of mature T cells in thymus (42), resembling a similar phenotype to S1P 1 receptor deficiency (1, 4) and FTY720 treatment (43). PKC inhibition also leads to S1P 1 receptor down-regulation, and FTY720 itself is a potent PKC inhibitor (Figs.…”

Section: Discussionmentioning

confidence: 99%

Down-regulation of S1P1 Receptor Surface Expression by Protein Kinase C Inhibition

Sensken

Gräler

2010

Journal of Biological Chemistry

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The sphingosine 1-phosphate receptor type 1 (S1P 1 ) is important for the maintenance of lymphocyte circulation. S1P 1 receptor surface expression on lymphocytes is critical for their egress from thymus and lymph nodes. Premature activation-induced internalization of the S1P 1 receptor in lymphoid organs, mediated either by pharmacological agonists or by inhibition of the S1P degrading enzyme S1P-lyase, blocks lymphocyte egress and induces lymphopenia in blood and lymph. Regulation of S1P 1 receptor surface expression is therefore a promising way to control adaptive immunity. Hence, we analyzed potential cellular targets for their ability to alter S1P 1 receptor surface expression without stimulation. The initial observation that preincubation of mouse splenocytes with its natural analog sphingosine was sufficient to block Transwell TM chemotaxis to S1P directed subsequent investigations to the underlying mechanism. Sphingosine is known to inhibit protein kinase C (PKC), and PKC inhibition with nanomolar concentrations of staurosporine, calphostin C, and GF109203X down-regulated surface expression of S1P 1 but not S1P 4 in transfected rat hepatoma HTC 4 cells. The PKC activator phorbol 12-myristate 13-acetate partially rescued FTY720-induced down-regulation of the S1P 1 receptor, linking PKC activation with S1P 1 receptor surface expression. FTY720, but not FTY720 phosphate, efficiently inhibited PKC. Cell-based efficacy was obvious with 10 nM FTY720, and in vivo treatment of mice with 0.3-3 mg/kg/day FTY720 showed increasing concentration-dependent effectiveness. PKC inhibition therefore may contribute to lymphopenia by down-regulating S1P 1 receptor cell surface expression independently from its activation.Lymphocyte circulation is dependent on cell surface expression of the S1P 1 2 receptor (1). Its endogenous ligand S1P serves as an exit signal in blood and lymph for lymphocytes that are leaving lymph nodes and thymus (2). The lymphocytes are thought to migrate from lymphoid organs with no or low S1P levels to blood and lymph with high S1P levels along a proposed S1P gradient (3). Deletion or down-regulation of the S1P 1 receptor in lymphocytes prevents their exit from thymus and lymph nodes and renders mice lymphopenic in blood and lymph (1, 4). Premature internalization of the S1P 1 receptor is induced by pharmacological agonists (5-7) and by inhibition or deletion of the S1P-degrading enzyme S1P-lyase (8, 9). In both cases the concentration of the endogenous or synthetic S1P 1 receptor agonist is predominantly increased in lymphoid organs and prevents re-expression of S1P 1 on the surface of lymphocytes (10). The exit signal S1P is consequently not recognized anymore, and lymphocytes are trapped in thymus and lymph nodes (11). Furthermore endothelial cells are stimulated via S1P 1 and close postulated endothelial cell barriers, again preventing lymphocytes from passing (12-14). Regulation of S1P 1 receptor surface expression is therefore crucial for maintaining lymphocyte circulation and immune surveillan...

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“…CD69 is an early activation marker that is transiently expressed on activated mature T cells. Although its function remains to be fully elucidated, a recent study based on CD69 transgenic mice suggest a role in the regulation of T cell trafficking [21]. In particular, CD69 expression prevented cells from migrating.…”

Section: Discussionmentioning

confidence: 99%

Frontline: Peripheral priming of alloreactive T cells by the direct pathway of allorecognition

2004

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Recent studies, though controversial, have suggested that secondary lymphoid organs may not constitute an essential site for the initiation of immune responses to transplant antigens. However, this issue has never been examined in the context of direct and indirect allorecognition. Here, we characterized immune responses arising in draining lymph nodes and skin allografts, in a murine model based on a single T cell clonotype where these two pathways can be independently studied. In this model, graft rejection by the direct or the indirect pathway occurred with similar kinetics, although initiation of the alloreactive responses was clearly different. During indirect responses, expansion and activation of alloreactive T cells were first observed in draining lymph nodes, at day 7 post-transplant, and graft-infiltrating T cells were observed later, at day 11. In striking contrast, directly activated alloreactive T cells were detected at an early stage inside the graft, and only later in the draining lymph nodes, after skin allograft rejection was almost completed. These results suggest that sensitization of naive T cells through the direct pathway could take place outside secondary lymphoid organs. See accompanying Commentary: http://dx

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A potential role for CD69 in thymocyte emigration

Cited by 133 publications

References 35 publications

Immunological memories of the bone marrow

Immunological memories of the bone marrow

Down-regulation of S1P1 Receptor Surface Expression by Protein Kinase C Inhibition

Frontline: Peripheral priming of alloreactive T cells by the direct pathway of allorecognition

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