Cutting Edge: CD4+ T Cell Help Can Be Essential for Primary CD8+ T Cell Responses In Vivo

Wang, Jyh-Chiang E.; Livingstone, Alexandra

doi:10.4049/jimmunol.171.12.6339

Cited by 148 publications

(121 citation statements)

References 25 publications

(38 reference statements)

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“…The role of CD4 ϩ T cell help in CD8 ϩ T cell responses is under active investigation, and the need for such help appears to depend on the details of the experimental model (36 -38). Although there are models where CTL immunity is dependent on CD4 ϩ T cell help (39 -42) and on cross-priming via DC (36), recent data suggest that primary activation from naive CD8 ϩ T cells can be helper independent, resulting in effector cells (38,43,44). Helper independence of CD8 ϩ T cells can occur at high precursor frequencies and can still generate a CTL response (45); however, such a helper-independent response may be defective in CD8 ϩ T cell memory development (43).…”

Section: Figurementioning

confidence: 99%

Local Intrahepatic CD8+ T Cell Activation by a Non-Self- Antigen Results in Full Functional Differentiation

Wuensch¹,

Pierce

Crispe³

2006

The Journal of Immunology

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The response of T cells to liver Ags sometimes results in immune tolerance. This has been proposed to result from local, intrahepatic priming, while the expression of the same Ag in liver-draining lymph nodes is believed to result in effective immunity. We tested this model, using an exogenous model Ag expressed only in hepatocytes, due to infection with an adeno-associated virus vector. T cell activation was exclusively intrahepatic, yet in contrast to the predictions of the current model, this resulted in clonal expansion, IFN-γ synthesis, and cytotoxic effector function. Local activation of naive CD8+ T cells can therefore cause full CD8+ T cell activation, and hepatocellular presentation cannot be used to explain the failure of CTL effector function against some liver pathogens such as hepatitis C.

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Section: Figurementioning

confidence: 99%

Local Intrahepatic CD8+ T Cell Activation by a Non-Self- Antigen Results in Full Functional Differentiation

Wuensch¹,

Pierce

Crispe³

2006

The Journal of Immunology

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“…Although CD4 ϩ T cell help is required for several aspects of CD8 ϩ T cell responses (76,77), the high frequency of Agspecific CD8 ϩ T cells in our adoptive transfer model may override a requirement for help (78), at least for initial proliferation of the cells.…”

Section: Discussionmentioning

confidence: 96%

Paternal Antigen-Bearing Cells Transferred during Insemination Do Not Stimulate Anti-Paternal CD8+ T Cells: Role of Estradiol in Locally Inhibiting CD8+ T Cell Responses

Seavey

Mosmann

2006

The Journal of Immunology

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Maternal immunological tolerance of the semiallogeneic fetus involves several overlapping mechanisms to balance maternal immunity and fetal development. Anti-paternal CD8+ T cells are suppressed during pregnancy in some but not all mouse models. Since semen has been shown to mediate immune modulation, we tested whether exposure to paternal Ag during insemination activated or tolerized anti-paternal CD8+ T cells. The uterine lumen of mated female mice contained male MHC I+ cells that stimulated effector, but not naive, CD8+ T cells ex vivo. Maternal MHC class I+ myeloid cells fluxed into the uterine lumen in response to mating and cross-presented male H-Y Ag to effector, but not naive, CD8+ T cells ex vivo. However, neither unprimed nor previously primed TCR-transgenic CD8+ T cells specific for either paternal MHC I or H-Y Ag proliferated in vivo after mating. These T cells subsequently responded normally to i.p. challenge, implicating ignorance rather than anergy as the main reason for the lack of response. CD8+ T cells responded to either peptide Ag or male cells delivered intravaginally in ovariectomized mice, but this response was inhibited by systemic estradiol (inducing an estrus-like state). Subcutaneous Ag induced responses in both cases. Allogeneic dendritic cells did not induce responses intravaginally even in ovariectomized mice in the absence of estradiol. These results suggest that inhibition of antiallogeneic responses is restricted both locally to the reproductive tract and temporally to the estrous phase of the menstrual cycle, potentially decreasing the risk of maternal immunization against paternal Ags during insemination.

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“…Thus, fewer studies have focused on the CD4 + T cell help requirement for the primary CD8 + T cell response. While majority of these suggested no impairment of CD8 + T cell priming in the absence of CD4 + T cell help [6,7,[14][15][16]], a few studies using primarily non-inflammatory stimuli suggested that CD4 + T cell help was absolutely or partially required for the generation a primary CD8 + T cell response [17][18][19][20][21]. Examples of the help-dependent model systems include immunization with peptide-pulsed wild-type DC injected into MHC class II-deficient mice or MHC class II-negative DC injected into normal mice [20], and immunization of CD4 -/-mice with Listeria monocytogenes secreting chicken ovalbumin [21].…”

mentioning

confidence: 99%

“…While majority of these suggested no impairment of CD8 + T cell priming in the absence of CD4 + T cell help [6,7,[14][15][16]], a few studies using primarily non-inflammatory stimuli suggested that CD4 + T cell help was absolutely or partially required for the generation a primary CD8 + T cell response [17][18][19][20][21]. Examples of the help-dependent model systems include immunization with peptide-pulsed wild-type DC injected into MHC class II-deficient mice or MHC class II-negative DC injected into normal mice [20], and immunization of CD4 -/-mice with Listeria monocytogenes secreting chicken ovalbumin [21].One of the main difficulties in assessing the developmental progression of primary CD8 + T cell responses is the low frequency of naive antigen-specific precursors. With naive T cell frequencies estimated to be less than 1 in 10 5 lymphoid cells [22], monitoring acute expansion of this population is difficult even when utilizing the current state-of-art techniques such as reactivity with MHC/peptide tetrameric complexes or using sensitive ELISPOT and intracellular cytokine staining assays.…”

mentioning

confidence: 99%

Altered primary CD8⁺ T cell response to a modified virus Ankara(MVA)‐vectored vaccine in the absence of CD4⁺ T cell help

Estcourt¹,

McMichael²,

Hanke³

2005

Eur J Immunol

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T cell receptor-transgenic F5 mice were used to assess primary CD8 + T cell responses to a modified virus Ankara (MVA)-vectored vaccine in the absence of CD4 + T cell help. Naive, CD8-enriched, CFSE-labelled F5 cells were transferred into normal or CD4 + celldepleted mice and the mice were vaccinated with MVA.HIVA-NP. At different time points during the primary response, F5 cells were re-isolated and analysed on divisional basis for a number of parameters. We demonstrated that the primary CD8 + T cell response in the absence of CD4 + T cell help differed from that in normal CD4 + cellundepleted mice. While in the absence of CD4 + T cell help, the initial migratory progress from the local response to a systemic one was not grossly affected, the proportion of dying F5 cells during the expansion phase was markedly increased and resulted in an overall smaller expansion and significantly decreased frequency of CD8 + T cell memory after contraction. T cells primed without help displayed accelerated proliferation and activation, while expression of interferon-c remained similar. These phenomena were observed in the lymph nodes draining the MVA.HIVA-NP immunization site and were similar, but delayed by 2-3 days in spleen and non-draining lymph nodes. IntroductionCD8 + T cells form an important part of the immune defence against many intracellular pathogens including viruses. Historically, CD8 + T cell responses against viral infections were considered to be independent from 'help' provided by CD4 + T cells. This was explained by direct activation of antigen-presenting DC by viruses, which provided ligands for Toll-like receptors and proinflammatory signals [1][2][3]. Recently, this view was revised by studies of non-inflammatory antigens which suggested that while primary CD8 + T cell response was CD4 + T cell-independent, secondary CD8 + T cell response, i.e. development of functional memory, was dependent on CD4 + T cell help during priming. These data led to the formulation of a programming model [4][5][6]. In contrast, another set of recent studies pointed towards an environmental model and proposed that CD4 + T cells were required to enhance survival of fully functional memory CD8 + T cells rather than imparting essential programming during the primary response [7,8]. The differences in these conclusions may be explained by the use of different antigens and immunization protocols, which might lead to differential activation of DC. Collectively, these and other experiments [9][10][11][12][13] not required for triggering the CD8 + T cell program of multiple cell divisions, effector function maturation and cell number contraction, but was needed for differentiation into functional CD8 + T cell memory and/or its maintenance.To date, most studies investigated secondary responses to make conclusions about the dependence of the CD8 + T cell responses on CD4 help. This is partially because induction of a good memory is the ultimate aim of a successful vaccination, but also because primary CD8 + T cell responses to non-inf...

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Cutting Edge: CD4+ T Cell Help Can Be Essential for Primary CD8+ T Cell Responses In Vivo

Cited by 148 publications

References 25 publications

Local Intrahepatic CD8+ T Cell Activation by a Non-Self- Antigen Results in Full Functional Differentiation

Local Intrahepatic CD8+ T Cell Activation by a Non-Self- Antigen Results in Full Functional Differentiation

Paternal Antigen-Bearing Cells Transferred during Insemination Do Not Stimulate Anti-Paternal CD8+ T Cells: Role of Estradiol in Locally Inhibiting CD8+ T Cell Responses

Altered primary CD8⁺ T cell response to a modified virus Ankara(MVA)‐vectored vaccine in the absence of CD4⁺ T cell help

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Cutting Edge: CD4+ T Cell Help Can Be Essential for Primary CD8+ T Cell Responses In Vivo

Cited by 148 publications

References 25 publications

Local Intrahepatic CD8+ T Cell Activation by a Non-Self- Antigen Results in Full Functional Differentiation

Local Intrahepatic CD8+ T Cell Activation by a Non-Self- Antigen Results in Full Functional Differentiation

Paternal Antigen-Bearing Cells Transferred during Insemination Do Not Stimulate Anti-Paternal CD8+ T Cells: Role of Estradiol in Locally Inhibiting CD8+ T Cell Responses

Altered primary CD8+ T cell response to a modified virus Ankara(MVA)‐vectored vaccine in the absence of CD4+ T cell help

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Altered primary CD8⁺ T cell response to a modified virus Ankara(MVA)‐vectored vaccine in the absence of CD4⁺ T cell help