Immunosuppressive activity of recombinant ILT3

Area of Science:

• Immunology
• Cell Biology

Background:

• Tolerogenic antigen presenting cells (APC) are crucial for immune homeostasis.
• High expression of inhibitory receptors ILT3 and ILT4 characterizes tolerogenic APCs.

Purpose of the Study:

• To investigate the extracellular signaling capacity of ILT3 and ILT4.
• To determine the role of the cytoplasmic regions of ILT3 and ILT4 in immune suppression.

Main Methods:

• Engineering of ILT3 and ILT4 cytoplasmic deletion mutants (ILT3delta and ILT4delta).
• Transfection of mutants into the dendritic-like cell line KG1.
• Assessment of T cell responses, including proliferation and cytotoxicity, and differentiation of CD8+ T regulatory cells.

Main Results:

• KG1.ILT3delta retained the inhibitory function of untruncated ILT3 on T cell proliferation and cytotoxicity.
• KG1.ILT4delta lost the suppressive activity of untruncated ILT4, indicating reliance on its cytoplasmic region.
• Recombinant soluble ILT3 inhibited T helper and cytotoxic functions and induced CD8+ T regulatory cell differentiation.

Conclusions:

• The inhibitory function of ILT4 is dependent on its cytoplasmic ITIM motifs.
• ILT3 can signal extracellularly to inhibit T cell responses and promote T regulatory cell generation.
• A feedback loop exists where T regulatory cells modulate APCs to induce inhibitory receptors, perpetuating immune tolerance.