Relative roles of T-cell receptor ligands and interleukin-2 in driving T-cell proliferation

Chakrabarti, Ranjana; Kumar, Sanjeev; Chakrabarti, Rabindranath

doi:10.1002/(sici)1097-4644(20000101)76:1<37::aid-jcb5>3.0.co;2-6

Cited by 9 publications

(7 citation statements)

References 24 publications

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“…Cytokines clearly play an important role in allowing survival and proliferation of activated T cells, and it has been shown that cytokine-mediated signals can control lymphocyte proliferation by regulating the expression of cell cycle proteins that control entry into the S phase of the cell cycle (22). We have shown that provision of at least IL-2 is necessary in our in vitro system, which is consistent with other studies demonstrating its importance in T cell proliferation (23)(24)(25). However, other cytokines such as IL-7 and/or IL-15, which have been recently implicated in regulating naive and memory T cell homeostasis (11)(12)(13)(14), may play important roles for in vivo T cell expansion following antigenic stimulation.…”

Section: Discussionsupporting

confidence: 91%

Cutting Edge: Antigen-Independent CD8 T Cell Proliferation

Wong

Pamer

2001

The Journal of Immunology

247

174

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Recent analyses of CD8 T cell responses to Listeria monocytogenes infection demonstrate that the duration of in vivo T cell proliferation is not determined by the amount or duration of Ag presentation. However, the extent to which T lymphocytes are capable of proliferating in the absence of Ag is unknown. Herein we demonstrate that CD8 T lymphocytes undergo up to eight rounds of proliferation in the absence of Ag following transient, 2.5-h in vitro antigenic stimulation. Ag-independent expansion of CD8 T cells is driven by IL-2 and is further augmented by IL-7 or IL-15. These experiments clearly demonstrate that CD8 T cells undergo prolonged proliferation following transient Ag exposure and support the notion that in vivo CD8 T cell expansion following infection can be uncoupled from Ag presentation.

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Section: Discussionsupporting

confidence: 91%

Cutting Edge: Antigen-Independent CD8 T Cell Proliferation

Wong

Pamer

2001

The Journal of Immunology

247

174

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“…Nef not only interferes with activation of p56 lck and as a consequence signaling via the IL-2R (52), but also hinders cell cycle progression by down-regulating cyclins D1 and A (53). Reduced production of IL-2 by CD4 ϩ T cells from the Tg mice may also have contributed to defective proliferation of these cells in vitro because T cells require IL-2 to complete the late portion of the G 1 phase and enter the S phase of the cell cycle (54). Proliferative responses to mitogens (55), C. albicans Ags (56), and stimulation with anti-CD3 (57) are all impaired in patients infected with HIV, accompanied by impaired induction of the early activation marker CD69 (57) and diminished IL-2 production (58).…”

Section: Discussionmentioning

confidence: 99%

Altered CD4+ T Cell Phenotype and Function Determine the Susceptibility to Mucosal Candidiasis in Transgenic Mice Expressing HIV-1

Lewandowski¹,

Marquis²,

Aumont³

et al. 2006

The Journal of Immunology

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The impairments of protective mucosal immunity which cause susceptibility to oropharyngeal candidiasis (OPC) in HIV infection remain undefined. This study used a model of OPC in CD4C/HIV MutA transgenic (Tg) mice expressing Rev, Env, and Nef of HIV-1 to investigate the role of transgene expressing dendritic cells (DCs) and CD4+ T cells in maintenance of chronic oral carriage of Candida albicans. DCs were depleted in the Tg mice and had an immature phenotype, with low expression of MHC class II and IL-12. CD4+ T cells were quantitatively reduced in the oral mucosa, cervical lymph nodes (CLNs) and peripheral blood of the Tg mice, and displayed a polarization toward a nonprotective Th2 response. Proliferation of CLN CD4+ T cells from infected Tg mice in response to C. albicans Ag in vitro was abrogated and the cells failed to acquire an effector phenotype. Coculture of C. albicans-pulsed DCs with CD4+ T cells in vitro showed that Tg expression in either or both of these cell populations sharply reduced the proliferation of CD4+ T cells and their production of IL-2. Finally, transfer of naive non-Tg CD4+ T cells into these Tg mice restored proliferation to C. albicans Ag and sharply reduced oral burdens of C. albicans. Overall, these results indicate that defective CD4+ T cells primarily determine the susceptibility to chronic carriage of C. albicans in these Tg mice.

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“…Although we have not examined NFAT activation in DKO T cells, our finding of normal IL-2 production suggests that any potential decrease in NFAT activation does not affect IL-2 secretion by these cells. Interaction of IL-2 with its high-affinity receptor induces further up-regulation of CD25 and delivers critical proliferation signals (24). WT and WASP KO T cells that had been first activated with OVAp then washed and stimulated with exogenous IL-2 further up-regulated CD25 expression (Fig.…”

Section: Dko T Cells Express Il-2 Receptor (Il-2r) and Secrete Il-2 Nmentioning

confidence: 98%

WIP is critical for T cell responsiveness to IL-2

Bras

Massaad

Suresh

et al. 2009

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

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T cell dysfunction is an important component of WAS and is involved in the susceptibility of WAS patients to recurrent infections, autoimmunity, and development of B cell malignancies. T cells from WAS patients and WASP KO mice fail to spread, cap their T cell antigen receptor (TCR), proliferate, and secrete IL-2 in response to TCR triggering by immobilized anti-CD3 (3, 4). Although WASP localizes with F-actin at the immune synapse (IS) (5), recent data suggest that IS formation may not be impaired in WASP KO T cells, but that WASP is essential for the stability of the IS during its reformation in naïve T cells (6). In addition to its role in T cell activation, WASP plays a role in T cell chemotaxis. T cells from WAS patients have defective chemotaxis in response to stromal cell derived factor-1␣ (7) and have defective transcellular diapedesis (8). WASP KO T cells have a defect in their ability to home in vivo to spleen and lymph nodes (9).In T cells, most of WASP is associated with the WASPinteracting protein (WIP) (10). WIP is ubiquitously expressed, but its expression is higher in lymphoid tissues. WIP, like WASP, plays an important role in T cell activation. Our previous work has shown that WIP KO T cells fail to proliferate, secrete IL-2, or increase their F-actin content after TCR ligation with immobilized anti-CD3 and have a homing defect in vivo (9, 11). WASP protein levels, but not mRNA levels, are severely diminished (down to 10% of normal) in T cells from WIP KO mice and WAS patients with mutations that disrupt WIP binding (8). Furthermore, WASP levels can be restored to normal by expressing WIP in WIP KO T cells, indicating that WIP stabilizes WASP in T cells. Similar observations were made in WIP knockdown experiments (12) and WIP-deficient dendritic cells (DCs) (13). WIP also stabilizes actin filaments (14). WIP KO, but not WASP KO, T cells, have defective F-actin increase after TCR ligation, disrupted actin cytoskeleton, and deficient IS formation (6,8,11), suggesting a role for WIP in actin-dependent T cell functions.A better understanding of the individual roles of WIP and WASP in T cell activation is crucial for elucidating the molecular pathology of WAS. WASP-deficient patients and mice have normal levels of WIP and have been instrumental in defining the individual role of WASP in T cell function. The severelydecreased level of WASP in WIP KO mice has limited their usefulness in defining the individual role of WIP in T cell function. To define this role, we generated WIP/WASP double KO (DKO) mice and compared their T cells with those of WASP KO mice. We reasoned that differences between WIP/WASP DKO T cells and WASP KO T cells would reflect WIP functions that are independent of WASP. We demonstrate that WIP plays, independently of WASP, a critical role in T cell activation by antigen, IL-2 signaling and responsiveness, and cytoskeletal rearrangement. Results and DiscussionThymic Development Is Normal, but the Number of Peripheral T Cells Is Reduced in DKO Mice. We analyzed T cell development i...

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Relative roles of T-cell receptor ligands and interleukin-2 in driving T-cell proliferation

Cited by 9 publications

References 24 publications

Cutting Edge: Antigen-Independent CD8 T Cell Proliferation

Cutting Edge: Antigen-Independent CD8 T Cell Proliferation

Altered CD4+ T Cell Phenotype and Function Determine the Susceptibility to Mucosal Candidiasis in Transgenic Mice Expressing HIV-1

WIP is critical for T cell responsiveness to IL-2

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