Modulation of γδ T cells
The present invention relate to the discovery that BTLA, IL-7 and RORγt modulate the activity and expression of γδT cells. Specifically, the present invention provides methods of modulating γδT cell homeostasis and function by regulating expression of BTLA. The present invention further provides agents which modulate the activity and expression of BTLA, RORyt and IL-7 and methods for screening of such agents. The present invention also provides methods for treating autoimmune or inflammatory diseases using modulators of BTLA, RORyt and IL-7.
1. A method of treating an inflammatory or autoimmune disease in a subject in need thereof comprising administering to the subject one or more agents that inhibit retinoid-related orphan receptor gamma-isoform-t (RORγt) expression or activity and/or increase IL-7 expression or activity, thereby treating the inflammatory or autoimmune disease, wherein the one or more agents is a RORγt siRNA comprising SEQ ID NO:22.
2. The method of claim 1 , wherein the one or more agents increases B and T lymphocyte attenuator (BTLA) expression or activity.
3. The method of claim 1 , wherein the one or more agents modulates the production of IL-17 or TNF by γδT cells.
4. The method of claim 1 , wherein the one or more agents modulates the levels of RORγt − γδT cells or RORγt − γδT cells.
5. The method of claim 1 , wherein one agent increases BTLA expression or activity and a second agent inhibits RORγt expression or activity.
6. The method of claim 1 , wherein the one or more agents inhibits herpes virus entry mediator (HVEM)-BTLA interactions.
7. The method of claim 1 , wherein the inflammatory or autoimmune disease is selected from the group consisting of psoriasis, multiple sclerosis, type I diabetes, dermatitis, celiac disease, and rheumatoid arthritis.
8. The method of claim 1 , further comprising administering IL-7 to the subject.
9. A method of modulating the level and/or activity of γδT cells comprising administering an agent that modulates B- and T-lymphocyte attenuator (BTLA) expression or activity, wherein the agent increases IL-7 expression or activity or inhibits RORγt expression or activity, wherein the agent is a RORγt siRNA comprising SEQ ID NO:22.
10. The method of claim 9 , wherein the agent increases BTLA expression or activity and increases the level and/or activity of γδT cells.
11. The method of claim 10 , wherein the agent inhibits HVEM-BTLA interactions.
12. The method of claim 9 , further comprising administering IL-7.
13. A method of modulating γδT cell production of IL-17 or TNF comprising administering an agent that modulates B- and T-lymphocyte attenuator (BTLA) expression or activity, wherein the agent increases IL-7 expression or activity or inhibits RORγt expression or activity, wherein the agent is a RORγt siRNA comprising SEQ ID NO:22.
14. The method of claim 13 , wherein the agent increases BTLA expression or activity and decreases γδT cell production of IL-17 or TNF.
15. The method of claim 14 , wherein the agent inhibits HVEM-BTLA interaction.
16. The method of claim 13 , further comprising administering IL-7.