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CD40 preferentially costimulates activation of CD4+ T lymphocytes
M Cayabyab1, J H Phillips, L L Lanier
1DNAX Research Institute of Molecular and Cellular Biology, Department of Immunology, Palo Alto, CA 94304.
Insights
CD40 ligand (CD40L) interactions costimulate T cell proliferation, particularly in CD4+ T cells, suggesting a role in T cell activation and differentiation. This pathway selectively expands CD4+ T cells via CD40-bearing antigen-presenting cells.
Area of Science:
- Immunology
- Cell Biology
Background:
- CD40 is a B cell antigen that promotes growth and Ig synthesis upon ligation.
- CD40 ligand (CD40L) is induced on T cells after activation.
- The CD40-CD40L interaction's role in T cell costimulation was investigated.
Purpose of the Study:
- To investigate the reciprocal costimulation of T cells by CD40-CD40L interactions.
- To determine the impact of CD40 costimulation on T cell proliferation and activation.
Main Methods:
- Genetic transfection of murine cells with CD40.
- Co-culture of human T cells with CD40+ transfectants and anti-CD3 antibody.
- Analysis of T cell proliferation, CTL generation, and cytokine dependence (IL-2).
- Comparison with other costimulatory molecules (VCAM-1, B7).
Main Results:
- CD40+ transfectants significantly augmented anti-CD3 induced T cell proliferation and CTL generation.
- T cell proliferation was IL-2 dependent.
- CD4+ T cells showed preferential proliferation compared to CD8+ T cells.
- Naive, memory, and cord blood T cells responded to CD40 costimulation.
Conclusions:
- The CD40-CD40L pathway costimulates T cell proliferation and CTL generation.
- CD40 costimulation preferentially expands CD4+ T cells.
- This pathway may play a role in T cell differentiation and activation, especially with CD40-bearing antigen-presenting cells.
Abstract:
CD40 is a membrane differentiation antigen constitutively expressed on B cells that induces B cell growth and Ig synthesis after ligation with anti-CD40 mAb or with the recently identified CD40 ligand (CD40L). CD40L is rapidly induced on T cells after activation with anti-CD3 mAb or mitogens. While CD40-CD40L interactions are clearly beneficial to B cells, we speculated that a reciprocal costimulation of T cells might also occur. We have used genetic transfection to demonstrate that interactions between human small, resting T cells and CD40+ murine transfectants substantially augmented anti-CD3 induced T cell proliferation and resulted in the generation of CTL. T cell proliferation costimulated by CD40 was IL-2 dependent. The ability of CD40+ transfectants to costimulate T cell proliferation was specific in that VCAM-1+, CD54+, CD72+, CD56+, CD31+, and fas+ transfectants in the same host cells were inactive. CD4+ T cells preferentially responded to CD40 costimulation, whereas CD8+ T cells were substantially less reactive. By contrast, costimulation with B7 transfectants induced equivalent proliferation in the CD4+ and CD8+ T cell subsets. In addition, adult naive and memory T cells, as well as cord blood T cells, were responsive to CD40. These findings suggest that the CD40-CD40L costimulation pathway may allow for selective expansion of CD4+ T cells after interaction with CD40-bearing APC. The relatively restricted expression of CD40 on APC, as well as on medullary and cortical thymic epithelium, indicates a possible role for this interaction in T cell differentiation and activation.