Human memory T cell differentiation into Th2-like effector cells is dependent on IL-4 and CD28 stimulation and inhibited by TCR ligation

Schulze‐Koops, Hendrik; Lipsky, Peter E.; Davis, Laurie S.

doi:10.1002/(sici)1521-4141(199808)28:08<2517::aid-immu2517>3.0.co;2-5

Cited by 32 publications

(49 citation statements)

References 39 publications

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“…In studies of human T cells activated with anti-CD3, Th2 effector cells were dependent on CD28 ligation but were inhibited by increased signal via the TCR, again suggesting that lower binding potential of the MHC-peptide-TCR complex would favor Th2 cell development (14). To study the Ag-specific human CD4 ϩ T cell response, we have examined the activation requirements and affinity of memory T cells which respond to the same peptide-MHC complex but are committed to either Th1 or Th2 lineage.…”

Section: T He Differentiation Of Naive Cd4 ϩ Th Cells Into Th1 Andmentioning

confidence: 99%

Differential Antigen Sensitivity and Costimulatory Requirements in Human Th1 and Th2 Antigen-Specific CD4+ Cells with Similar TCR Avidity

Holzer

Kwok

Nepom

et al. 2003

The Journal of Immunology

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The differentiation of naive CD4+ Th cells into Th1 and Th2 phenotypes is influenced by cytokines, concentration of Ag, accessory molecules, and the affinity of the MHC-TCR interaction. To study these factors in human memory T cells, T cell lines with Th1 or Th2 phenotypes specific for the peptide hemagglutinin (HA)307–319 in the context of DRB1*0401 were established from the peripheral blood of an individual previously vaccinated for influenza virus. Flow cytometric analysis with fluorescent-labeled MHC class II tetramers was used to analyze TCR avidity: the Th2 line bound the HLA-DR*0401-HA307–319 tetramers with higher mean avidity, although the range of binding avidity largely overlapped with the Th1 line. High-affinity Th1 and Th2 lines were established for further study by FACS sorting. When activated with plate-bound HLA-DR*0401-HA307–319 monomers, the Th1 line proliferated and produced IFN-γ without additional costimulation whereas the Th2 line required the addition of soluble anti-CD28 Ab to induce proliferation and IL-5 production, but this requirement could be overcome with high concentrations of plate-bound monomer alone. IL-2 production was dependent on costimulation in both cell lines. These findings demonstrate that upon antigenic rechallenge, Th1 and Th2 cells differ in their response to Ag-specific stimulation. Th2 cells were sensitive to the strength of signal to a greater degree than Th1 cells and required costimulation through CD28 for maximal proliferation. These distinctions between Th1 and Th2 activation are not consistent with a simple avidity model of Ag recognition and indicate both qualitative and quantitative differences in determining cell lineage commitment.

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Section: T He Differentiation Of Naive Cd4 ϩ Th Cells Into Th1 Andmentioning

confidence: 99%

Differential Antigen Sensitivity and Costimulatory Requirements in Human Th1 and Th2 Antigen-Specific CD4+ Cells with Similar TCR Avidity

Holzer

Kwok

Nepom

et al. 2003

The Journal of Immunology

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“…Cells were washed with PBS and incubated with SRBC (30). The rosette-positive cells were further purified by negative selection using saturating amounts of mAbs against CD8, CD16, CD19, CD56, HLA-DR, and CD45RA (for the purification of memory CD4 T cells) or CD45RO (for the purification of naive CD4 T cells), followed by panning on plastic petri dishes coated with goat anti-mouse Igs (Cappel, West Chester, PA) for 15 min at room temperature as previously described (14,31). Recovered cells were washed with PBS and resuspended in RPMI 1640 (Life Technologies) containing 10% normal human serum (NHS).…”

Section: Cell Purificationmentioning

confidence: 99%

“…T cell differentiation was assessed employing an in vitro, multiple-step differentiation system as previously described (14,32). Briefly, freshly isolated, naive CD4 T cells (CD4 ϩ CD45RA ϩ ) (0.5 ϫ 10 6 /ml) were primed by plate-bound OKT3 (1 g/ml) and anti-CD28 mAb (1 g/ml) in the presence of rIL-2 (10 U/ml), in the presence or the absence of A77 1726, and where indicated in the presence of 50 M UTP (Amersham Pharmacia Biotech, Piscataway, NJ).…”

Section: In Vitro T Cell Differentiationmentioning

confidence: 99%

“…In some experiments freshly isolated naive CD4 T cells were primed in the presence of IL-12 (40 ng/ml) and anti-IL-4 (10 g/ml; Th1-inducing conditions) or in the presence of IL-4 (31.5 ng/ml) and anti-IL-12 (100 ng/ml; Th2-inducing conditions). After 5 days of priming, the cells were harvested, washed, counted, and rested for 2.5 days at 37°C at a concentration of 1 ϫ 10 6 cells/ml in medium supplemented with a nonmitogenic concentration of rIL-2 (10 U/ml) to maintain cell viability (14). Differentiated CD4 T cells were harvested, washed, and assessed for their ability to produce cytokines by intracellular flow cytometry.…”

Section: In Vitro T Cell Differentiationmentioning

confidence: 99%

“…Several in vivo and in vitro experiments emphasize the role of the intensity of T cell stimulation in the outcome of Th differentiation. For example, in an Ag-independent in vitro system, increasing TCR stimulation with a mAb to the ⑀-chain of the TCR complex in the presence of constant costimulation enhanced IFN-␥ production of memory CD4 T effectors and Th1 differentiation in a dose-dependent manner (14). Likewise, high doses of Ag (15), a high affinity of peptide/MHC class II/TCR interactions (16,17), and increasing intensities of Ag presentation (18) favor Th1 differentiation.…”

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confidence: 99%

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Restriction of De Novo Pyrimidine Biosynthesis Inhibits Th1 Cell Activation and Promotes Th2 Cell Differentiation

Dimitrova

Skapenko

Herrmann³

et al. 2002

The Journal of Immunology

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Leflunomide, an inhibitor of de novo pyrimidine biosynthesis, has recently been introduced as a treatment for rheumatoid arthritis in an attempt to ameliorate inflammation by inhibiting lymphocyte activation. Although the immunosuppressive ability of leflunomide has been well described in several experimental animal models, the precise effects of a limited pyrimidine supply on T cell differentiation and effector functions have not been elucidated. We investigated the impact of restricted pyrimidine biosynthesis on the activation and differentiation of CD4 T cells in vivo and in vitro. Decreased activation of memory CD4 T cells in the presence of leflunomide resulted in impaired generation and outgrowth of Th1 effectors without an alteration of Th2 cell activation. Moreover, priming of naive T cells in the presence of leflunomide promoted Th2 differentiation from uncommitted precursors in vitro and enhanced Th2 effector functions in vivo, as indicated by an increase in Ag-specific Th2 cells and in the Th2-dependent Ag-specific Ig responses (IgG1) in immunized mice. The effects of leflunomide on T cell proliferation and differentiation could be antagonized by exogenous UTP, suggesting that they were related to a profound inhibition of de novo pyrimidine biosynthesis. These results indicate that leflunomide might exert its anti-inflammatory activities in the treatment of autoimmune diseases by preventing the generation of proinflammatory Th1 effectors and promoting Th2 cell differentiation. Moreover, the results further suggest that differentiation of CD4 T cells can be regulated at the level of nucleotide biosynthesis.

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Triggering of T cell proliferation through CD28 induces GATA‐3 and promotes T helper type 2 differentiationin vitroandin vivo

et al. 1999

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The relative contribution of T cell receptor‐versus CD28‐mediated signals in co‐stimulation of resting CD4 T cells is thought to influence their functional differentiation towards T helper (Th) 1 versus Th2 subsets. We have used a conventional and a mitogenic CD28‐specific monoclonal antibody to assess the effect of polyclonal T cell activation through CD28 alone on CD4 subset differentiation. In vivo, mitogenic but not conventional anti‐CD28 induces massive lymphocytosis, the Th2 cytokines interleukin (IL)‐4 and IL‐10, and Th2‐dependent immunoglobulin isotypes, most notably IgE. In vitro, it is shown that mitogenic anti‐CD28 primes for IL‐4‐dependent induction of IL‐4 expression much more efficiently than conventional co‐stimulation. At the molecular level, we show for the first time that the activation of the “Th2 promoting” transcription factor GATA‐3 requires co‐stimulation by CD28 and is also induced by mitogenic anti‐CD28 alone. We suggest that CD28‐dependent induction of GATA‐3 in concert with other transcription factors, which are preferentially induced by strong CD28‐signals, primes CD4 T cells for IL‐4‐dependent Th2 differentiaton.

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Human memory T cell differentiation into Th2-like effector cells is dependent on IL-4 and CD28 stimulation and inhibited by TCR ligation

Cited by 32 publications

References 39 publications

Differential Antigen Sensitivity and Costimulatory Requirements in Human Th1 and Th2 Antigen-Specific CD4+ Cells with Similar TCR Avidity

Differential Antigen Sensitivity and Costimulatory Requirements in Human Th1 and Th2 Antigen-Specific CD4+ Cells with Similar TCR Avidity

Restriction of De Novo Pyrimidine Biosynthesis Inhibits Th1 Cell Activation and Promotes Th2 Cell Differentiation

Triggering of T cell proliferation through CD28 induces GATA‐3 and promotes T helper type 2 differentiationin vitroandin vivo

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