Mechanisms of deficient interferon-gamma production in atopic diseases.

BACKGROUND: The mechanisms responsible for an imbalanced cytokine response in atopic diseases are still not understood. While impaired interferon-gamma (IFN-gamma) production may be the result of a pathological T-cell/antigen-presenting cell (APC) interaction, evidence was provided that the T cell itself may have an intrinsic defect to produce IFN-gamma. OBJECTIVE: To clarify whether impaired IFN-gamma production by T cells from patients with atopic dermatitis (AD) represents an intrinsic defect in producing IFN-gamma. METHODS: Effector T cells were generated from CD4+ CD45RA+-naive precursors from patients with AD and healthy control individuals by activation with anti-CD3+ anti-CD28 MoAbs. Following restimulation, IFN-gamma production was measured by ELISA and flow cytometry. RESULTS: IFN-gamma production by atopic T cells was decreased compared with healthy T cells. IL-12 present at priming or high doses of IL-2 during the culture period, even in the absence of IL-12, completely restored IFN-gamma production. Conversion of naive CD45RA+ to CD45R0+ effector cells did not differ between atopic and healthy donors' T cells. CONCLUSION: Impaired IFN-gamma production by T cells from atopic individuals is not the result of an intrinsic, genetically fixed, defect to produce sufficient amounts of IFN-gamma. The data provides evidence that correction of an impaired TH1 response in AD may be successful at the precursor T cell level.

IFN-gamma is only partially restored by co-stimulation with IL-12, IL-2, IL-15, IL-18 or engagement of CD28.

BACKGROUND: Although it is well established that T cells derived from patients with atopic diseases produce low levels of interferon-gamma (IFN-gamma), the mechanisms responsible for this phenomenon are poorly understood. OBJECTIVES: To elucidate whether IFN-gamma production may be restored by co-stimulatory molecules known to increase IFN-gamma production in vitro. Further, to investigate whether deficient IFN-gamma production is associated with disease activity. METHODS: Purified peripheral T cells obtained from patients with severe atopic dermatitis (AD), individuals with a history but no symptoms of AD and healthy control subjects were activated with anti-CD3 MoAbs in the presence or absence of anti-CD28 MoAbs, interleukin (IL-) 12, IL-2, IL-15 or IL-18. IFN-gamma production was determined at the single cell level by flow cytometry, as well as by ELISA. RESULTS: Activated T cells from patients with severe AD produced less IFN-gamma than T cells from healthy control individuals. IL-12 or engagement of CD28 enhanced IFN-gamma production in both healthy and atopic T cells. However, absolute values of IFN-gamma were still different. IL-2, IL-15 and IL-18 did not restore IFN-gamma production. T cells from individuals with a history of AD produced more IFN-gamma than those from subjects with severe AD, but less than T cells from healthy individuals. Atopic T cells expressed regular levels of CD3, CD28 and Stat4, the main signal transducer and activator of transcription for IL-12. IL-4, IL-10 and TGF-beta production by T cells were not different between healthy and atopic individuals. CONCLUSION: IFN-gamma deficiency in atopic T cells is not due to a lack of responsiveness to CD28, IL-12, IL-2, IL-15 or IL-18. T cell-derived cytokines able to antagonize IFN-gamma do not contribute to decreased IFN-gamma production. The extent of IFN-gamma deficiency seems to be dependent on disease activity.