Immune cell-derived C3a and C5a costimulate human T cell alloimmunity.

Area of Science:

• Immunology
• Complement System Biology
• T Cell Activation

Background:

• Complement's role in T cell costimulation is established in mice but unclear in humans.
• Human T cells and dendritic cells express complement receptors C3aR and C5aR.

Purpose of the Study:

• To investigate the impact of complement activation products (C3a, C5a) on human T cell responses.
• To determine the role of antigen-presenting cells as a source of complement.
• To evaluate the therapeutic potential of targeting complement receptors in vivo.

Main Methods:

• In vitro co-culture of human T cells and dendritic cells.
• Use of complement receptor antagonists and recombinant complement proteins.
• siRNA knockdown of complement components and regulatory proteins.
• In vivo studies using a mouse model of graft-versus-host disease.

Main Results:

• C3a and C5a promote human T cell proliferation and CD4(+) T cell expansion.
• Complement receptor blockade inhibits T cell alloresponses and AKT phosphorylation.
• Antigen-presenting cells are identified as the primary source of complement.
• Pharmacological C5aR blockade reduces graft-versus-host disease severity and improves survival in mice.

Conclusions:

• Complement-derived C3a and C5a act as crucial costimulatory signals for human T cells.
• Targeting C3aR and C5aR represents a promising therapeutic strategy for immune-mediated diseases like GVHD and transplant rejection.