Modulating protective and pathogenic CD4+ subsets via CD137 in type 1 diabetes.

Area of Science:

• Immunology
• Autoimmune Diseases
• T-cell Biology

Background:

• CD137 (TNFRSF9) is a T-cell costimulatory molecule implicated in autoimmune diabetes.
• The Idd9.3 interval in NOD mice contains candidate genes for autoimmune diabetes, including CD137.

Purpose of the Study:

• To investigate the role of CD137 in the development of autoimmune diabetes in NOD mice.
• To determine the therapeutic potential of anti-CD137 treatment in preventing or delaying diabetes onset.

Main Methods:

• Treatment of NOD mice with anti-CD137 antibodies.
• T-cell transfer studies using CD4(+) and CD8(+) cells from treated mice into NOD-scid recipients.
• Analysis of immune cell populations, including CD4(+)CD25(+)Foxp3(+) regulatory T-cells, and their suppressive activity.

Main Results:

• Anti-CD137 treatment protected NOD mice from diabetes but not insulitis.
• Transfer of CD4(+) cells from treated mice delayed diabetes onset.
• Increased CD4(+)CD25(+)Foxp3(+) regulatory T-cells with enhanced suppressive activity were observed in treated mice.
• Disease onset was hastened when anti-CD137 was administered to recipients of diabetic spleen cells, indicating a balance-dependent effect.

Conclusions:

• CD137 plays a critical role in the early phase of autoimmune diabetes by promoting regulatory T-cell production.
• Anti-CD137 immunotherapy holds potential for treating type 1 diabetes, contingent on the balance between pathogenic and protective immune cells.
• Disease-associated CD137 alleles may be insufficient for generating adequate regulatory T-cell responses to prevent autoimmune diabetes.