Finding balance in the immune system: Mechanisms that regulate infection and cancer

Effective functioning of the immune system relies upon systems of checks and balances; too little activity results in overwhelming infection, too much activity results in excessive damage to the host. The importance of balance is particularly notable in cancers of the immune system, such as Cutaneous T-cell Lymphoma (CTCL), a cancer of skin-homing T-lymphocytes. Advanced CTCL causes inflammatory tissue damage in CTCL-involved skin and defects in cell-mediated immunity that lead to frequent Staphylococcus aureus (S. aureus) skin and soft tissue infections (SSTI) associated with high morbidity and mortality. The mechanisms that lead to defects in cell-mediated immunity and inflammatory tissue damage in CTCL remain poorly defined. We previously identified high levels of LAIR2, a decoy protein for the inhibitory immune receptor LAIR1, in advanced CTCL. Available evidence supports the notion that LAIR proteins likely function in inflammatory responses in infection, including RSV infection, severe COVID-19, and pediatric malarial infection. Given their immunosuppressive function and high expression in some hematologic malignancies, LAIR proteins have also been evaluated as targets for cancer therapy. Mice do not have a LAIR2 homolog, so we used Lair1 knock-out (KO) mice to model LAIR2 overexpression. In a model of subcutaneous S. aureus skin infection, Lair1 KO mice had significantly larger abscesses and areas of dermonecrosis compared to WT. Lair1 KO exhibited a pattern of increased inflammatory responses in infection and sterile immune stimulation, including increased production of proinflammatory cytokines and myeloid chemokines, neutrophil ROS, and collagen/ECM remodeling pathways. CTCL skin lesions harbored similar patterns of increased expression in cytokine and collagen/ECM remodeling pathways, suggesting that high levels of LAIR2 in CTCL recapitulates Lair1 KO, causing inflammatory tissue damage and compromising host defense against S. aureus infection.

Learning Objectives:

1. Describe the role of LAIR proteins in regulating immune responses during bacterial infection and cancer.

2. Explain how Lair1 knock-out mouse models are used to study the effects of LAIR2 overexpression on inflammation and host defense.

3. Analyze the parallels between immune dysregulation in Lair1 KO mice and inflammatory tissue damage observed in advanced cutaneous T-cell lymphoma (CTCL).