IL-12 Is Required for Induction but Not Maintenance of Protective, Memory Responses to <i>Blastomyces dermatitidis</i>: Implications for Vaccine Development in Immune-Deficient Hosts

Wüthrich, Marcel; Warner, Thomas T.; Klein, Bruce S.

doi:10.4049/jimmunol.175.8.5288

Cited by 30 publications

(20 citation statements)

References 51 publications

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“…It is evident that most immunological adjuvants activate innate immune cells by pathogen-associated molecular patterns for TLRs leading to the generation of a costimulatory context capable of promoting T cell activation, proliferation, and differentiation that produces effector and memory T cells (7)(8)(9). However, recently chronic inflammation, typically characterized by abundant IL-12 production, has been shown to restrict CD8 T cell clonal expansion and memory generation (10).…”

Section: T He Cd8mentioning

confidence: 99%

IL-12-Programmed Long-Term CD8+ T Cell Responses Require STAT4

Li¹,

Eppolito²,

Odunsi

et al. 2006

The Journal of Immunology

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Immunological adjuvants activate innate immune cells for Ag presentation and elicitation of cytokines like IL-12 that promote T cell expansion and effector differentiation. An important but elusive aim for most immunization strategies is to produce memory T cells that provide durable immunity. Recent evidence demonstrates that the context of Ag presentation instructionally programs T cells for short- and long-term responses. However, the role and mechanisms by which cytokines like IL-12 condition CD8 T cells for long-term responses remain relatively uncharacterized. In this study, we show that brief exposure (20 h) of naive TCR-transgenic CD8 cells to IL-12 during Ag stimulation leads to transient phosphorylation of STAT4 for robust effector differentiation. Moreover, the IL-12-induced STAT4 engenders greater clonal expansion of the Ag-activated CD8 cells by regulating the expression of the transcriptional factor Bcl3- and Bcl2-related genes that promote survival of Ag-activated CD8 cells. Remarkably, the IL-12-conditioned CD8 T cells demonstrate increased sensitivity to IL-7 and IL-15, whereby they are rendered “fit” for homeostatic self-renewal as well as augmented CD4-dependent recall responses that are effective at controlling Salmonella infection in vivo. This information provides new insights into mechanisms by which IL-12 conditions CD8 T cells for long-term immunity, which is likely to benefit development of new strategies for the use of IL-12 in infectious diseases and cancer.

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Section: T He Cd8mentioning

confidence: 99%

IL-12-Programmed Long-Term CD8+ T Cell Responses Require STAT4

Li¹,

Eppolito²,

Odunsi

et al. 2006

The Journal of Immunology

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“…IL-12 is required for induction but not maintenance of memory T1 (type 1 T cell) responses [24]. Based on our data, we suspect that LV-SOCS1-siRNA-DCs produced more IL-12 in a feedback loop-enhanced manner to help induce the memory responses we saw.…”

Section: Discussionmentioning

confidence: 59%

“…Since IL-2, IL-7, IL-12, and IL-15 are important cytokines for memory T cell production and homeostasis [24,25], we hypothesized that downregulating the production of SOCS1 in dendritic cells might allow increased signaling to T cells by these and other cytokines, resulting in expanded memory Tcell populations. Enhanced antigen presentation by SOCS1-downregulated dendritic cells should also boost memory T cell production.…”

Section: Introductionmentioning

confidence: 99%

SOCS1 downregulation in dendritic cells promotes memory T-cell responses

Aldrich

Sanders

Lapteva

et al. 2008

Vaccine

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SOCS1-1 is crucial for control of immune cell cytokine expression, including those cytokines known to enable memory T cell formation and homeostasis. In this study, we found that immunization with SOCS1-downregulated bone marrow-derived dendritic cells generated increased antigen-specific CD8 + T memory cells and antigen-specific responses, as measured by ELISPOT, CTL assays, serum ELISAs, and T-cell proliferation assays. Bone marrow-derived dendritic cells in which SOCS1 was downregulated expressed increased levels of surface IL-15Ra and thymic leukemia (TL) antigen, both of which support memory cell development. This work supports a crucial role for SOCS1 in regulation of dendritic cell-directed generation of memory T cell responses.

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“…However, these factors, and even CD4 cells themselves (34), are dispensable in immunodeficient mice, illustrating the plasticity of vaccine immunity at both the cellular and the molecular levels (34,35). We have recently observed that interleukin-12 (IL-12) is required for the induction, but not maintenance, of protective memory responses against B. dermatitidis infection (36). Dispensability of IL-12 during the maintenance phase of antifungal memory immunity was unexpected and, to our knowledge, was not previously established during CMI to infectious diseases.…”

Section: Discussionmentioning

confidence: 99%

CD28 Is Required for Optimal Induction, but Not Maintenance, of Vaccine-Induced Immunity toBlastomyces dermatitidis

Wüthrich¹,

Warner²,

Klein

2005

Infect Immun

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Cellular immunity mediated by T lymphocytes, in particular CD4؉ and CD8 ؉ type 1 cells, is the main defense against pathogenic fungi. Here, CD28-deficient (CD28 ؊/؊ ) mice were used to study the role of costimulation for the generation and maintenance of T-cell-mediated, type 1 cytokine-dependent mechanisms of vaccine immunity to Blastomyces dermatitidis infection. Disruption of CD28 costimulation reduced the number of type 1 CD4 and CD8 cells generated and impaired resistance to infection. Type 1 T-cell subsets generated in vaccinated CD28 ؊/؊ mice were durable and protected mice for at least 3 months after vaccination. Our findings suggest that CD28 is required for the induction of optimal, protective T-cell responses to B. dermatitidis infection but may be dispensable for the maintenance of T-cell memory.Protective immunity to infections with endemic fungi, including Blastomyces dermatitidis, is thought to require type 1-dependent cell-mediated immunity (CMI) responses (10,11,33,35) and can be mediated by both vaccine-induced CD4 ϩ (35) and CD8 ϩ T cells (34) that produce type 1 cytokines, particularly gamma interferon (IFN-␥) and tumor necrosis factor alpha (TNF-␣). To uncover the molecular requirement that lead to effective generation and maintenance of memory T cells, we investigated the role of B7:CD28 costimulation for the activation of CD4 and CD8 T cells in vaccine-induced immunity to B. dermatitidis infection.It is now accepted that the engagement of the T-cell receptor (TCR) by peptide/major histocompatibility complex (signal 1) is generally not sufficient to trigger a T-cell response and that ligation of a costimulatory receptor(s) (signal 2) is required (17,19,24,31). Indeed, signaling via the TCR alone can induce a state of anergy in naive CD4 ϩ T cells in certain situations (4, 5). The most-studied costimulatory molecules are B7-1 (CD80) and B7-2 (CD86), which bind to the counterreceptors CD28 and CTLA-4 at the T-cell surface. The B7-1/ B7-2:CD28/CTLA-4 costimulatory pathway has received considerable attention as a regulatory control point in T-cell responses. The low levels of B7-1 and B7-2 on immature antigen-presenting cells (APC) are upregulated after activation and interact with positive (CD28) or negative (CTLA-4) receptors on T cells. Both B7 molecules are considered essential for induction of major histocompatibility complex class IIrestricted T-cell responses (4). In support of this view, CD4 T-cell responses to lymphocytic choriomeningitis virus (9, 20), herpes simplex virus type 1 (13), and influenza virus (3) are greatly reduced in CD28 Ϫ/Ϫ mice. Conversely, parasitic infection with Leishmania major (7), Toxoplasma gondii (30), and Heligmosomoides polygyrus (15) activates CD4 cells independently of CD28/B7 interaction.The role of B7 costimulation in the initiation of CD8 responses in vivo is less clear. In cases where the CD8 response occurs through a CD4-dependent pathway of APC activation, it is held that APC conditioning involves costimulatory signaling via CD40-CD40L and B7-CD28. ...

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IL-12 Is Required for Induction but Not Maintenance of Protective, Memory Responses to Blastomyces dermatitidis: Implications for Vaccine Development in Immune-Deficient Hosts

Cited by 30 publications

References 51 publications

IL-12-Programmed Long-Term CD8+ T Cell Responses Require STAT4

IL-12-Programmed Long-Term CD8+ T Cell Responses Require STAT4

SOCS1 downregulation in dendritic cells promotes memory T-cell responses

CD28 Is Required for Optimal Induction, but Not Maintenance, of Vaccine-Induced Immunity toBlastomyces dermatitidis

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