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Distinct effects of CD86-mediated costimulation on resting versus activated human CD4+ T cells
Nicola J Rogers1, David S Game, Niels O S Camara
1Department of Immunology, Imperial College of Science, Technology and Medicine, London, UK.
Insights
CD80 and CD86 costimulate T cells, but CD86 is less effective for memory T cells and can be inhibitory. CTLA-4 signaling may override CD86 costimulation in activated T cells.
Area of Science:
- Immunology
- Cellular immunology
- T cell activation
Background:
- CD80 and CD86 are critical B7 costimulatory molecules for initiating T cell immunity.
- The functional differences between CD80 and CD86, beyond expression patterns, are not fully understood.
- Understanding these differences is key to deciphering T cell immune responses.
Purpose of the Study:
- To investigate the distinct functional roles of CD80 and CD86 in human CD4+ T cell costimulation.
- To compare the costimulatory capacity of CD80 and CD86 on naïve, memory, and activated T cells.
- To elucidate the impact of CD80/CD86 co-expression and CTLA-4 ligation on T cell responses.
Main Methods:
- Utilized HLA-DR1 transfectants expressing CD80, CD86, or both as stimulators.
- Tested responses of unseparated peripheral blood CD4+ T cells, separated memory T cells, and human T cell clones.
- Employed anti-CD86 antibody and anti-CTLA-4 Fab to assess inhibitory effects and signaling pathways.
Main Results:
- Both CD80 and CD86 costimulated unseparated CD4+ T cells, but CD86 was less effective on memory T cells and T cell clones.
- CD80/CD86 double transfectants showed reduced responses in clones compared to CD80 alone, suggesting CD86 can be inhibitory.
- Addition of anti-CTLA-4 Fab restored T cell proliferation when CD86 was present, indicating CTLA-4 dominance.
Conclusions:
- CD80 and CD86 deliver distinct signals to previously activated T cells.
- CD86 exhibits inhibitory functions in certain contexts, particularly with memory T cells and T cell clones.
- CTLA-4 ligation can override CD86-mediated costimulation in activated CD4+ T cells.
Abstract:
CD80 and CD86 are important in the initiation of T cell immunity. Although their costimulatory function has long been appreciated, it remains unclear whether the biological significance of the two B7 isoforms resides in their different patterns and kinetics of expression or whether differences exist in their function. We have addressed this issue using HLA-DR1 transfectants co-expressing CD80, CD86, or both molecules as stimulators for naïve, memory, and activated human CD4+ T cells. Both CD80 and CD86 efficiently costimulated alloresponses by unseparated peripheral blood CD4+ T cells; however, CD86 was substantially inferior in costimulating alloresponses by separated memory T cells, and completely incompetent in costimulating three human T cell clones. Furthermore, CD80/CD86 double transfectants stimulated lower responses by the clones than cells expressing CD80 alone. That CD86 was actively inhibitory rather than merely neutral was evidenced by the increase in response to the double CD80/CD86 APC when anti-CD86 antibody was added. Furthermore, addition of anti-CTLA-4 Fab to cultures of HLA-DR1 transfectants co-expressing CD86, fully restored the proliferative response. These results indicate that CD80 and CD86 mediate distinct signals in previously activated T cells, and demonstrate that CTLA-4 ligation may dominate the outcome of CD86-mediated costimulation of activated CD4+ T cells.
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