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A biomimetic five-module chimeric antigen receptor (5MCAR) designed to target and eliminate antigen-specific T cells
Shio Kobayashi1,2, Martin A Thelin1, Heather L Parrish2
1Section of Immunobiology, Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215.
Abstract:
T cells express clonotypic T cell receptors (TCRs) that recognize peptide antigens in the context of class I or II MHC molecules (pMHCI/II). These receptor modules associate with three signaling modules (CD3γε, δε, and ζζ) and work in concert with a coreceptor module (either CD8 or CD4) to drive T cell activation in response to pMHCI/II. Here, we describe a first-generation biomimetic five-module chimeric antigen receptor (5MCAR). We show that 1) chimeric receptor modules built with the ectodomains of pMHCII assemble with CD3 signaling modules into complexes that redirect cytotoxic T lymphocyte (CTL) specificity and function in response to the clonotypic TCRs of pMHCII-specific CD4+ T cells, and 2) surrogate coreceptor modules enhance the function of these complexes. Furthermore, we demonstrate that adoptively transferred 5MCAR-CTLs can mitigate type I diabetes by targeting autoimmune CD4+ T cells in NOD mice. This work provides a framework for the construction of biomimetic 5MCARs that can be used as tools to study the impact of particular antigen-specific T cells in immune responses, and may hold potential for ameliorating diseases mediated by pathogenic T cells.
Insights
Researchers developed a novel five-module chimeric antigen receptor (5M-CAR) to redirect T cell responses. This biomimetic receptor targets autoimmune T cells, showing potential for treating type I diabetes and other immune-mediated diseases.
Area of Science:
- Immunology
- Molecular Biology
- Biotechnology
Background:
- T cells utilize T cell receptors (TCRs) to recognize antigens presented by MHC molecules.
- TCRs associate with CD3 signaling modules and coreceptors (CD4 or CD8) for T cell activation.
- Current therapies often lack specificity in targeting pathogenic T cells.
Purpose of the Study:
- To develop and characterize a first-generation biomimetic five-module chimeric antigen receptor (5M-CAR).
- To assess the ability of 5M-CARs to redirect T cell specificity and function.
- To evaluate the therapeutic potential of 5M-CARs in an autoimmune disease model.
Main Methods:
- Construction of chimeric receptor modules using pMHCII ectodomains.
- Assembly of 5M-CARs with CD3 signaling modules and surrogate coreceptors.
- Testing 5M-CAR functionality in redirecting cytotoxic T lymphocyte (CTL) specificity.
- Adoptive transfer of 5M-CAR-engineered CTLs in NOD mice to assess type I diabetes mitigation.
Main Results:
- Chimeric receptor modules incorporating pMHCII ectodomains successfully assemble with CD3 signaling modules.
- 5M-CARs redirect CTL specificity and function towards pMHCII-specific CD4+ T cells.
- Surrogate coreceptor modules enhance the functionality of 5M-CAR complexes.
- Adoptively transferred 5M-CAR-CTLs demonstrated efficacy in mitigating type I diabetes in NOD mice by targeting autoimmune CD4+ T cells.
Conclusions:
- Biomimetic 5M-CARs provide a framework for engineering antigen-specific T cell responses.
- These CARs can be utilized as tools to study T cell-mediated immune responses.
- 5M-CARs hold potential for therapeutic applications in diseases driven by pathogenic T cells, such as type I diabetes.
