Journal
JOURNAL OF IMMUNOLOGY
Volume 190, Issue 4, Pages 1416-1423Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1201620
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Funding
- National Institutes of Health [U19 AI 57266, U19 AI090019, R01 AR42527, R01 EY11916, R01 AI44142, P01 HL058000]
- Veterans Affairs Merit Award [BX001669]
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Regulation of the ERK pathway is intimately involved in determining whether TCR stimulation is productive or induces anergy. T cells from patients with rheumatoid arthritis (RA) have increased ERK responsiveness, which may be relevant for disease pathogenesis. Inflammatory cytokines such as TNF-alpha did not reproduce the TCR hypersensitivity typical for RA in T cells from healthy individuals. In contrast, priming with the homeostatic cytokines (HCs) IL-7 and IL-15 amplified ERK phosphorylation to TCR stimulation 2- to 3-fold. The underlying mechanism involved a priming of the SOS-dependent amplification loop of RAS activation. The sensitization of the TCR signaling pathway has downstream consequences, such as increased proliferation and preferential Th1 differentiation. Importantly, priming with IL-7 or IL-15 enabled T cell responses to autoantigens associated with RA. Production of HCs is induced in lymphopenic conditions, which have been shown to predispose for autoimmunity and which appear to be present in the preclinical stages of RA. We propose that HCs, possibly induced by lymphopenia, decrease the signaling threshold for TCR activation and are thereby partly responsible for autoimmunity in RA. The Journal of Immunology, 2013, 190: 1416-1423.
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