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CD4-mediated signals induce T cell dysfunction in vivo
N Chirmule1, A Avots, S M LakshmiTamma
1Institute for Human Gene Therapy, University of Pennsylvania, Philadelphia 19104, USA. chirmule@mail.med.upenn.edu
Abstract:
Triggering of CD4 coreceptors on both human and murine T cells can suppress TCR/CD3-induced secretion of IL-2. We show here that pretreatment of murine CD4+ T cells with the CD4-specific mAb YTS177 inhibits the CD3-mediated activation of the IL-2 promoter factors NF-AT and AP-1. Ligation of CD4 molecules on T cells leads to a transient stimulation of extracellular signal-regulated kinase (Erk) 2, but not c-Jun N-terminal kinase (JNK) activity. Pretreatment with anti-CD4 mAb impaired anti-CD3-induced Erk2 activation. Costimulation with anti-CD28 overcame the inhibitory effect of anti-CD4 Abs, by induction of JNK activation. The in vivo relevance of these studies was demonstrated by the observation that CD4+ T cells from BALB/c mice injected with nondepleting anti-CD4 mAb were inhibited in their ability to respond to OVA Ag-induced proliferation and IL-2 secretion. Interestingly, in vivo stimulation with anti-CD28 mAb restored IL-2 secretion. Furthermore, animals pretreated with anti-CD4 elicited enhanced IL-4 secretion induced by OVA and CD28. These observations suggest that CD4-specific Abs can inhibit T cell activation by interfering with signal 1 transduced through the TCR, but potentiate those delivered through the costimulatory molecule CD28. These studies have relevance to understanding the mechanism of tolerance induced by nondepleting anti-CD4 mAb used in animal models for allograft studies, autoimmune pathologies, and for immunosuppressive therapies in humans.
Insights
Anti-CD4 antibodies inhibit T cell activation by interfering with T cell receptor (TCR) signaling. However, they can enhance responses mediated by the CD28 costimulatory molecule, impacting immune tolerance and therapies.
Area of Science:
- Immunology
- Molecular Biology
- Cellular Signaling
Background:
- CD4 coreceptors can suppress T cell receptor (TCR)/CD3-induced interleukin-2 (IL-2) secretion in human and murine T cells.
- Understanding the precise mechanisms of CD4-mediated regulation of T cell activation is crucial for developing targeted immunotherapies.
Purpose of the Study:
- To investigate how CD4-specific monoclonal antibodies (mAbs) affect T cell activation pathways, specifically the IL-2 promoter factors NF-AT and AP-1.
- To elucidate the role of CD4 ligation in the activation of extracellular signal-regulated kinase (Erk) 2 and c-Jun N-terminal kinase (JNK) signaling.
- To determine the in vivo relevance of anti-CD4 mAb effects on T cell proliferation, IL-2 secretion, and cytokine profiles, and the impact of CD28 costimulation.
Main Methods:
- Pretreatment of murine CD4+ T cells with anti-CD4 mAb (YTS177) followed by stimulation with anti-TCR/CD3.
- Analysis of NF-AT and AP-1 activation, and Erk2 and JNK kinase activity.
- In vivo studies using BALB/c mice injected with anti-CD4 mAb, assessing T cell proliferation, IL-2, and IL-4 secretion in response to OVA antigen and anti-CD28 mAb.
Main Results:
- Anti-CD4 mAb inhibited CD3-mediated activation of NF-AT and AP-1, and impaired anti-CD3-induced Erk2 activation.
- CD28 costimulation overcame anti-CD4 inhibition by inducing JNK activation.
- In vivo, anti-CD4 mAb inhibited OVA-induced T cell proliferation and IL-2 secretion, but CD28 costimulation restored IL-2 secretion and enhanced IL-4 secretion.
Conclusions:
- CD4-specific antibodies inhibit T cell activation via TCR signaling but potentiate CD28-mediated costimulation.
- These findings provide insights into the mechanisms of tolerance induced by nondepleting anti-CD4 mAbs.
- The results have implications for understanding and developing immunosuppressive therapies for allograft rejection and autoimmune diseases.