Determinants of HIV-Specific CD8 T-cell responses in HIV-infected pediatric patients and enhancement of HIV-gag-specific responses with exogenous IL-15☆

Chitnis, Vivek; Pahwa, Rajendra; Pahwa, Savita

doi:10.1016/s1521-6616(02)00051-7

Cited by 31 publications

(22 citation statements)

References 50 publications

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“…Therefore, our data strongly suggest that modulation of lck expression is one of the key molecular events responsible for the well documented capacity of IL-15 and INF-␣ to promote both primary and memory CTL responses. IL-15 has been recently shown to augment CTL responses to HIV antigens both in experimental vaccination models and in peripheral blood mononuclear cells of AIDS patients where functional incapacity of HIV-specific CTLs represents a critical factor in the pathogenesis of the disease (39)(40)(41). Notably, IL-2 and IL-7 were significantly less potent (40).…”

Section: Discussionmentioning

confidence: 99%

“…IL-15 has been recently shown to augment CTL responses to HIV antigens both in experimental vaccination models and in peripheral blood mononuclear cells of AIDS patients where functional incapacity of HIV-specific CTLs represents a critical factor in the pathogenesis of the disease (39)(40)(41). Notably, IL-2 and IL-7 were significantly less potent (40). Because IL-15 and IFN-␣ are produced primarily by monocytes and different subsets of dendritic cells, the upregulation of lck by these lymphokines may represent one of the mechanisms responsible for the enhancing effect of innate immune activation on CTL responses.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Regulation of lck degradation and refractory state in CD8⁺cytotoxic T lymphocytes

Uhlin

Masucci²,

Levitsky³

2005

Proc. Natl. Acad. Sci. U.S.A.

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After specific activation, CD8 ؉ cytotoxic T lymphocytes (CTLs) enter a refractory state termed activation-induced nonresponsiveness (AINR) that is characterized by the inability of T cells to respond to a secondary stimulus. Here, we show that T cell receptor triggering results in rapid degradation of the src-family protein kinase lck through a mechanism that is proteasome-and lysosome-independent, sensitive to cysteine protease inhibitors, and distinct from the pathways involved in degradation of ZAP-70 kinase or -chain of the CD3 complex. Pharmacologic blockade of lck degradation, as well as transfection of refractory cells with an lck expression vector, increased responsiveness of CTLs to repeated antigenic challenge. The development or maintenance of AINR was not affected by exogenously added IL-2, whereas IL-15 or IFN-␣ restored both lck expression and responsiveness of preactivated CTLs. Our results suggest that lck degradation plays an important role in the development of AINR in human CTLs and that this condition can be reverted by pharmacologic agents or lymphokines that prevent lck degradation or induce its expression.ϩ T cells are driven into an anergic state by T cell receptor (TCR) triggering in the absence of costimulation. In contrast, CD8 ϩ cytotoxic T lymphocytes (CTLs) become unable to proliferate or produce IL-2 in response to specific stimulation subsequent to the primary TCR triggering combined with the engagement of costimulatory molecules, such as CD28 (1, 2). This functional condition of CTLs is often referred to as activation-induced nonresponsiveness (AINR) (3). In anergic CD4 ϩ T cells, expression of phospholipase C-␥1 (PLC-␥), protein kinase C (PKC)-⌰ and RasGTPase-activating protein (RASGAP) is down-regulated (4). Alterations in signal transduction were also reported in refractory CTLs (5) but the mechanisms responsible for the development and maintenance of AINR remain poorly defined. In mouse CTLs, AINR may be reverted by exogenous IL-2 (6) but it is not known whether the lymphokine acts in a similar way on human CTLs.One of the first molecules to be activated downstream of the TCR is lck, an src-family protein kinase, which is essential for normal development of CD4 and CD8 single positive thymocytes, proliferation of naïve mature T cells as well as functional activity of effector and memory T-lymphocytes (reviewed in ref. 7). During the process of T cell activation, lck acts both as a tyrosine kinase and adaptor molecule, which binds and phosphorylates a number of cell-surface and intracellular substrates. The activity and intracellular distribution of lck is regulated by several posttranslational modifications (for reviews, see refs. 7-9). In addition, the level of lck expression affects its net activity. Lck expression is often significantly decreased in lymphocytes infiltrating tumors or circulating in the blood of patients with chronic infections or inflammation (10-14) that may play a role in the functional incapacity of T cells observed during cancer progression or chronic...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Regulation of lck degradation and refractory state in CD8⁺cytotoxic T lymphocytes

Uhlin

Masucci²,

Levitsky³

2005

Proc. Natl. Acad. Sci. U.S.A.

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“…These doses for IL-2 and IL-15 have been reported as being optimal for preventing T cell apoptosis. 24 IFN-␥/IL-2 Secretion Assay. PBMCs (10 ϫ 10 6 ) were stimulated at 37°C with 10 g/mL HCV peptides or 1 g/mL proteins as used in the ELISpot assay for 6 hours and 16 hours, respectively.…”

Section: Methodsmentioning

confidence: 99%

Preferential loss of IL-2-secreting CD4+ T helper cells in chronic HCV infection

et al. 2005

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“…In vitro IL-15 enhances survival, inhibits CD95-induced apoptosis, and augments effector function of HIV-specific CD8 ϩ T cells (34,35). Furthermore, IL-15 stimulates expansion of HIVspecific CD8 ϩ T cells (36,37) and restores NK cytotoxicity and deficient IL-12 production by PBMC from HIV-infected individuals (19).…”

Section: Il-15 Treatment During Acute Simian Immunodeficiency Virus (mentioning

confidence: 99%

IL-15 Treatment during Acute Simian Immunodeficiency Virus (SIV) Infection Increases Viral Set Point and Accelerates Disease Progression despite the Induction of Stronger SIV-Specific CD8+ T Cell Responses

Mueller

Altork

et al. 2008

The Journal of Immunology

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In this study, we examined the effect of in vivo treatment of acutely SIV-infected Mamu-A*01+ rhesus macaques with IL-15. IL-15 treatment during acute infection increased viral set point by 3 logs and accelerated the development of simian AIDS in two of six animals with one developing early minimal lesion SIV meningoencephalitis. Although IL-15 induced a 2- to 3-fold increase in SIV-specific CD8+ T cell and NK cell numbers at peak viremia and reduced lymph node (LN) SIV-infected cells, this had no impact on peak viremia and did not lower viral set point. At viral set point, however, activated SIV-specific CD8+ T cells and NK cells were reduced in the blood of IL-15-treated animals and LN SIV-infected cells were increased. Week 30 LN from IL-15-treated animals had significantly increased Gag-specific CD8+ T cell numbers, whereas total cell, lymphocyte, and CD4+ T cell numbers were reduced. IL-15 treatment significantly reduced anti-SIV Ab concentrations at week 3 and viral set point. IL-15 increased Ki-67+CD4+ T cells at week 1 of treatment and reduced blood CCR5+ and CD45RA−CD62L− CD4+ T cells. The frequency of day 7 Ki-67+CD4+ T cells strongly correlated with viral set point. These findings suggest that CD4+ T cell activation during acute infection determines subsequent viral set point and IL-15 treatment by increasing such activation elevates viral set point. Finally, IL-15-treated acutely SIV-infected primates may serve as a useful model to investigate the poorly understood mechanisms that control viral set point and disease progression in HIV infection.

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Determinants of HIV-Specific CD8 T-cell responses in HIV-infected pediatric patients and enhancement of HIV-gag-specific responses with exogenous IL-15☆

Cited by 31 publications

References 50 publications

Regulation of lck degradation and refractory state in CD8⁺cytotoxic T lymphocytes

Regulation of lck degradation and refractory state in CD8⁺cytotoxic T lymphocytes

Preferential loss of IL-2-secreting CD4+ T helper cells in chronic HCV infection

IL-15 Treatment during Acute Simian Immunodeficiency Virus (SIV) Infection Increases Viral Set Point and Accelerates Disease Progression despite the Induction of Stronger SIV-Specific CD8+ T Cell Responses

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Determinants of HIV-Specific CD8 T-cell responses in HIV-infected pediatric patients and enhancement of HIV-gag-specific responses with exogenous IL-15☆

Cited by 31 publications

References 50 publications

Regulation of lck degradation and refractory state in CD8+cytotoxic T lymphocytes

Regulation of lck degradation and refractory state in CD8+cytotoxic T lymphocytes

Preferential loss of IL-2-secreting CD4+ T helper cells in chronic HCV infection

IL-15 Treatment during Acute Simian Immunodeficiency Virus (SIV) Infection Increases Viral Set Point and Accelerates Disease Progression despite the Induction of Stronger SIV-Specific CD8+ T Cell Responses

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Regulation of lck degradation and refractory state in CD8⁺cytotoxic T lymphocytes

Regulation of lck degradation and refractory state in CD8⁺cytotoxic T lymphocytes