The threshold for autoimmune T cell killing is influenced by B7-1

Area of Science:

• Immunology
• Autoimmunity
• T cell biology

Background:

• Naive T cell activation requires co-stimulatory signals.
• The role of co-stimulation during the effector phase of T cell responses is less understood.
• Autoimmunity to pancreatic islets involves T cell responses.

Purpose of the Study:

• To investigate the necessity of B7-1 (CD80) co-stimulation during the effector phase of autoimmune responses targeting pancreatic beta cells.
• To determine if B7-1 expression on target cells influences T cell-mediated destruction in autoimmune diabetes and potentially tumor immunotherapy.

Main Methods:

• Utilized transgenic mouse models expressing B7-1 in pancreatic beta cells, including "confluent" and "patchy" expression patterns.
• Introduced B7-1 transgene into both normal and nonobese diabetic (NOD) mouse backgrounds, often co-expressing IL-2.
• Assessed T cell reactivity, islet destruction, diabetes transfer, and syngeneic islet graft rejection.

Main Results:

• Transgenic B7-1 expression in islets co-expressing IL-2 led to spontaneous autoimmunity and beta cell destruction.
• Islet destruction and diabetes transfer required continuous B7-1 expression by target beta cells.
• T cell-mediated rejection of syngeneic islet grafts occurred only if grafts expressed B7-1.

Conclusions:

• Continuous B7-1 expression by target beta cells is essential for effector T cell-mediated islet destruction.
• Normally, beta cells do not express B7-1, rendering potentially reactive T cells harmless.
• Target cell B7-1 expression may be critical for T cell-mediated killing of poorly immunogenic targets, with implications for tumor immunotherapy.