Expression of a single ICAM-1 isoform on T cells is sufficient for development of experimental autoimmune
Daniel C Bullard1, Xianzhen Hu, David Crawford
1Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, USA.
Insights
Intercellular adhesion molecule-1 (ICAM-1) isoforms impact experimental autoimmune encephalomyelitis (EAE). A specific ICAM-1 variant lacking domain 4 drives demyelinating disease, suggesting it as a therapeutic target for multiple sclerosis.
Area of Science:
- Immunology
- Neuroscience
- Molecular Biology
Background:
- Intercellular adhesion molecule-1 (ICAM-1) is crucial for immune cell interactions and signaling.
- Alternative splicing generates at least seven ICAM-1 isoforms with largely unknown immunobiology.
- Previous studies indicated that ICAM-1 isoforms influence experimental autoimmune encephalomyelitis (EAE) progression.
Purpose of the Study:
- To investigate the role of specific ICAM-1 isoforms in the pathogenesis of demyelinating diseases.
- To determine if a particular ICAM-1 isoform can independently mediate EAE initiation and progression.
Main Methods:
- Utilized a novel transgenic mouse model (CD2-Icam1(D4del)/Icam1(null)) for T-cell-specific expression of an ICAM-1 isoform lacking Ig domain 4.
- Assessed the capacity of this specific ICAM-1 isoform to induce and sustain EAE.
Main Results:
- T-cell-specific expression of the ICAM-1 isoform (Ig domains 1, 2, 3, and 5) was sufficient to initiate and drive EAE.
- The ICAM-1 isoform lacking Ig domain 4 plays a significant role in the pathogenesis of demyelinating disease.
Conclusions:
- The ICAM-1 isoform lacking Ig domain 4 can independently mediate the development of EAE.
- This specific ICAM-1 isoform represents a potential novel therapeutic target for multiple sclerosis treatment.
Abstract:
Intercellular adhesion molecule-1 (ICAM-1) plays an important role in leukocyte trafficking, induction of cellular immune responses, and immunological synapse formation. As a member of the immunoglobulin superfamily of adhesion proteins, ICAM-1 is composed of repeating Ig-like domains, a transmembrane domain, and short cytoplasmic tail that participates in intracellular signaling events. At least seven ICAM-1 protein isoforms are generated by alternative splicing, however little is known regarding their immunobiology. We have previously shown using different lines of ICAM-1 mutant mice (Icam1(tm1Jcgr) and Icam1(tm1Bay) ) that expression of alternatively spliced ICAM-1 isoforms can significantly influence the disease course during the development of EAE. In this study, we show using a newly developed transgenic mouse (CD2-Icam1(D4del) /Icam1(null) ) that T-cell-specific expression of a single ICAM-1 isoform composed of Ig domains 1, 2, 3, and 5 can mediate the initiation and progression of EAE. Our results indicate that the ICAM-1 isoform lacking Ig domain 4 can drive pathogenesis in demyelinating disease and may be a novel therapeutic target for treating multiple sclerosis.
