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Augmentation of naive, Th1 and Th2 effector CD4 responses by IL-6, IL-1 and TNF
S B Joseph1, K T Miner, M Croft
1La Jolla Institute for Allergy and Immunology, Division of Immunochemistry, San Diego, USA.
Insights
Antigen-presenting cell (APC) cytokines boost naive T cell activation, especially with co-stimulation. However, these cytokines have limited effects on effector T cell differentiation and primarily enhance existing effector cell cytokine production.
Area of Science:
- Immunology
- Cellular Biology
- T cell Activation
Background:
- The precise role of cytokines secreted by antigen-presenting cells (APCs) in T cell activation remains incompletely understood and debated.
- T cell activation is a complex process involving signals from T cell receptors and co-stimulatory molecules, influenced by the cytokine milieu.
Purpose of the Study:
- To investigate the direct effects of exogenous cytokines (IL-6, IL-1, TNF) on naive and effector CD4 T cell subsets.
- To determine the requirement for co-signaling (via anti-CD28) in cytokine-mediated T cell responses.
- To elucidate the differential impact of these cytokines on naive T cell activation versus effector T cell differentiation and function.
Main Methods:
- Utilized highly purified naive, Th1, and Th2 CD4 T cell populations.
- Stimulated T cells with anti-CD3 antibody in the absence of APCs, with and without anti-CD28 co-stimulation.
- Assessed T cell proliferation, IL-2 secretion, and the production of other cytokines (IFN-gamma, IL-4, IL-5) in response to exogenous IL-6, IL-1, and TNF.
Main Results:
- Exogenous IL-6, IL-1, and TNF enhanced proliferation and IL-2 secretion from naive T cells, with IL-6 being most potent, particularly in combination with IL-1 or TNF.
- Naive T cell enhancement required co-stimulation via anti-CD28, indicating a crucial role for co-signaling in initiating IL-2 production.
- Cytokines had minimal impact on naive T cell differentiation into effector populations but augmented cytokine production (IFN-gamma, IL-5) from pre-existing Th1 and Th2 effector cells, also often requiring CD28 signaling.
Conclusions:
- APC-derived cytokines can directly promote T cell responses, primarily in naive T cells, and largely depend on co-stimulation through accessory co-receptors.
- The enhancing effects of these cytokines are not specific to a particular T cell subset or cytokine, with naive T cells being the principal target.
- While cytokines influence naive T cell activation and effector cell cytokine output, their role in driving effector cell differentiation is limited.
Abstract:
The role of antigen-presenting cell (APC)-derived cytokines in T cell activation is still controversial. Highly purified CD4 T cell populations of the naive and short-term Th1 and Th2 effector subsets were examined. Stimulation from anti-CD3 in the absence of APC was used to analyze directly T occurring cell-mediated effects, and the requirement for co-signaling was addressed using anti-CD28. Exogenous IL-6, IL-1 and TNF each enhanced proliferation and IL-2 secretion from naive cells, although IL-6 was most active in this regard. Peak responses, however, were obtained with IL-1 or TNF in combination with IL-6 resulting in up to 11-fold increases in IL-2 secretion. Enhanced naive T cell responses were only observed with anti-CD3 and anti-CD28, suggesting that co-signaling through surface-bound receptors was required to initiate IL-2 production. Although the cytokines enhanced naive activation, little effect was seen on differentiation into effector populations. IL-6 alone, or in combination, partially suppressed effectors secreting IFN-gamma, but did not promote generation of effectors secreting IL-4. In contrast to reports on cloned cell lines, IL-6, TNF and IL-1 had enhancing activities on all cytokines elicited from already generated Th1 and Th2 effector populations. Again combinations of IL-6, TNF and IL-1 were most effective and generally required CD28 signaling. Induced responses with preexisting effector cells were far less than with naive cells and predominantly directed at augmenting IFN-gamma and IL-5 secretion rather than IL-2 and IL-4. These studies show that APC-derived cytokines can promote T cell responses directly but largely after co-stimulation from accessory molecule co-receptors, that the effect is not specific for one T cell subset or cytokine, and that the naive T cell is the main target of action.