Differential T Cell Costimulatory Requirements in CD28-Deficient Mice

Shahinian, Arda; Pfeffer, Klaus; Lee, Kelvin P.; Kündig, Thomas M.; Kishihara, Kenji; Wakeham, Andrew; Kawai, Kazuhiro; Ohashi, Pamela S.; Thompson, Craig B.; Mak, Tak W.

doi:10.1126/science.7688139

Cited by 1,170 publications

(874 citation statements)

References 57 publications

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“…Costimulatory receptor for B7-1 and B7-2 involved in many T cell-dependent processes [46,47]. ICOS Costimulatory molecule of the CD28 family [48,49].…”

Section: Abbreviations Usedmentioning

confidence: 99%

Induction of granzyme B and T cell cytotoxic capacity by IL-2 or IL-15 without antigens: Multiclonal responses that are extremely lytic if triggered and short-lived after cytokine withdrawal

et al. 2006

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The purpose of these studies was to determine the minimal requirements to induce granzyme B, cytotoxic granules and perforin-dependent lytic capacity. To our surprise, both IL-2 and IL-15 induced not only proliferation, but also profound granzyme B and lytic capacity from CD8 + T cells in the absence of antigen or TCR-stimulation. Mouse splenocytes were incubated with mouse r-IL-2 or r-IL-15 for three days, tested by anti-CD3 redirected lysis and examined for intracellular granzyme B and for T cell activation markers. With 10 −8 M IL-2 or IL-15, there was excellent lytic activity at 1:1 effector to target ratios mediated by T cells from wild type but not from perforin-gene-ablated mice, consistent with multiclonal activation. Lower interleukin concentrations induced less lytic activity. Granzyme B was undetectable on day 0, and greatly elevated on day 3 in CD44 hi CD8 + T cells as detected by flow cytometry. Cytokines alone elevated the granzyme B as much as concanavalin A combined with the cytokines. Some ex vivo CD8 + T cells were CD122 + , as were the cultured granzyme B + cells, thus both populations had low affinity receptors for the interleukins. Only some of the activated cells were proliferating as detected by CFSE labeling. When the cytokines were withdrawn, the cells lost lytic activity within 24 hours and then within the next 24 hours, died. Our results suggest that high concentrations of either IL-2 or IL-15 will activate the lytic capacity and granzyme B expression of many T cells and that antigen recognition is not required.

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“…Costimulatory receptor for B7-1 and B7-2 involved in many T cell-dependent processes [46,47]. ICOS Costimulatory molecule of the CD28 family [48,49].…”

Section: Abbreviations Usedmentioning

confidence: 99%

Induction of granzyme B and T cell cytotoxic capacity by IL-2 or IL-15 without antigens: Multiclonal responses that are extremely lytic if triggered and short-lived after cytokine withdrawal

et al. 2006

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“…The role of CD28 in cell-mediated immunity is demonstrated by the CD28 gene-knockout mouse, which has an immunosuppressed phenotype, and CD28 Ϫ/Ϫ mouse T cells are unable to sustain activation and are susceptible to apoptosis (2,3). In various experimental systems, blockade of CD28 interaction with its ligands CD80 and CD86 has been demonstrated to dampen antigenspecific immune responses (4).…”

Section: Conclusion Overproduction Of Tnf␣ In Ra Induces a Global Domentioning

confidence: 99%

Modulation of CD28 expression with anti–tumor necrosis factor α therapy in rheumatoid arthritis

Bryl¹,

Vallejo²,

Matteson³

et al. 2005

Arthritis & Rheumatism

122

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Objective. The immune system of patients with rheumatoid arthritis (RA) is characterized by the accumulation of CD4؉ T cells deficient in CD28 expression and the up-regulation of tumor necrosis factor ␣ (TNF␣). Previous in vitro studies have shown that TNF␣ induces transcriptional silencing of the CD28 gene. Because reduced expression of CD28 in T cells compromises immunocompetence, we examined whether CD28 expression is reduced in patients with RA in vivo and whether the reduction is related to TNF␣.Methods. Patients with RA and age-matched individuals were recruited. Peripheral blood mononuclear cells were stained for CD3, CD4, CD8, CD28, TNF receptor I (TNFRI), and TNFRII, and analyzed by quantitative flow cytometry. The number of CD28 and TNFR molecules was monitored in a subgroup of patients with RA undergoing treatment with anti-TNF␣.Results. In addition to higher frequencies of CD28 null T cells, patients with RA had significantly reduced numbers of CD28 and TNFRI molecules on CD4؉,CD28؉ T cells. Normal expression could be restored in vitro by overnight culture, suggesting that CD28 in patients was modulated by exogenous factors. In contrast, treatment with TNF␣ in vitro resulted in further down-regulation. CD28 expression was normalized in patients undergoing TNF␣-neutralizing therapy.Conclusion. Overproduction of TNF␣ in RA induces a global down-regulation of CD28 in CD4؉ T cells and may cause reduced sensitivity to costimulatory signals in T cell responses.

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“…In the absence of an appropriate costimulation, TCR occupancy alone can lead to T-cell unresponsiveness or clonal anergy, in which T cells are unable to proliferate or secrete cytokines in response to a secondary stimulation (Schwartz, 1996). Consistent with this, CD28-negative transgenic mice exhibit profound defects in mitogenic responses (Shahinian et al, 1993), and germinal centres are not formed in response to immunisation (Ferguson et al, 1996).…”

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confidence: 99%

Alterations of the expression of T-cell-related costimulatory CD28 and downregulatory CD152 (CTLA-4) molecules in patients with B-cell chronic lymphocytic leukaemia

et al. 2004

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In the present study, we have examined the kinetics and magnitude of expression of the CD28 and CD152 molecules on unstimulated and anti-CD3 þ rIL-2-stimulated peripheral blood CD4 þ and CD8 þ T cells in patients with chronic lymphocytic leukaemia (B-CLL) and controls. The mean percentages of both CD3 þ /CD4 þ /CD28 þ and CD3 þ /CD8 þ /CD28 þ cells were significantly lower in B-CLL than in controls before culture, decreased rapidly, reaching their lowest levels between 24 and 48 h, and returned to basal levels after 72 h of culture. In controls, the lowest proportions of CD3 þ /CD4 þ /CD28 þ and CD3 þ /CD8 þ / CD28 þ cells were found after 24 h and returned to prestimulation levels after 48 h of stimulation. We observed significantly higher proportions of unstimulated CD3 þ /CD4 þ /CD152 þ and CD3 þ /CD8 þ /CD152 þ cells in B-CLL patients than in controls. The highest percentages of CD3 þ /CD4 þ /CD152 þ and CD3 þ /CD8 þ /CD152 þ cells were observed in controls after 72 h, and in B-CLL patients after 24 h, and remained statistically higher after 48, 72 and 96 h of stimulation. CD152 molecule expression returned to prestimulation levels after 96 h of culture in controls, and after 120 h in B-CLL patients. The abnormal kinetics and levels of CD28 and CD152 expression on T cells in B-CLL may lead to a state of hyporesponsiveness or anergy and could be one of the mechanisms of immune deficiency in this disease.

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Differential T Cell Costimulatory Requirements in CD28-Deficient Mice

Cited by 1,170 publications

References 57 publications

Induction of granzyme B and T cell cytotoxic capacity by IL-2 or IL-15 without antigens: Multiclonal responses that are extremely lytic if triggered and short-lived after cytokine withdrawal

Induction of granzyme B and T cell cytotoxic capacity by IL-2 or IL-15 without antigens: Multiclonal responses that are extremely lytic if triggered and short-lived after cytokine withdrawal

Modulation of CD28 expression with anti–tumor necrosis factor α therapy in rheumatoid arthritis

Alterations of the expression of T-cell-related costimulatory CD28 and downregulatory CD152 (CTLA-4) molecules in patients with B-cell chronic lymphocytic leukaemia

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