CTLA-4-B7 interaction is sufficient to costimulate T cell clonal expansion

Area of Science:

• Immunology
• Molecular Biology
• Cellular Biology

Background:

• T cell costimulation is crucial for immunity, involving B7 family ligands (B7-1, B7-2) and T cell receptors (CD28, CTLA-4).
• CD28-B7 interaction is thought to promote T cell responses, while B7-CTLA-4 interaction is believed to downregulate them.
• Direct verification of individual receptor responses to B7 ligands has been lacking.

Purpose of the Study:

• To directly verify the roles of CD28 and CTLA-4 in T cell costimulation by B7-1.
• To investigate the costimulatory activity of CTLA-4 independent of CD28.
• To elucidate the combined effect of CD28 and CTLA-4 in B7-mediated T cell activation.

Main Methods:

• Utilizing CD28-deficient T cells to assess B7-1 costimulatory activity.
• Employing intact and Fab fragments of anti-CTLA-4 monoclonal antibodies (mAbs) for blockade studies.
• Using a mutant B7-1 molecule (B7W88>A) with selective binding affinities for CD28 and CTLA-4.

Main Results:

• B7-1 promotes T cell clonal expansion even in the absence of CD28, indicating a CD28-independent costimulatory pathway mediated by CTLA-4.
• This CD28-independent costimulation by B7-1 is completely inhibited by anti-CTLA-4 mAb.
• A B7-1 mutant lacking CD28 binding but retaining CTLA-4 binding also promotes T cell clonal expansion.
• While CD28 enhances the T cell response to B7-1, this enhanced response is also fully blocked by anti-CTLA-4 mAb.

Conclusions:

• B7-CTLA-4 interaction actively promotes T cell clonal expansion, challenging the traditional view of CTLA-4 as solely inhibitory.
• Optimal T cell responses to B7 ligands are achieved through the combined engagement of both CD28 and CTLA-4.
• CTLA-4 plays a significant role in promoting T cell activation, suggesting a revised understanding of its function in immune responses.