Provided herein are compositions and methods for modulation of immune response via PYRIN domain-only proteins POP1 and/or POP3. In particular, POP1 and/or POP3 are inhibited to enhance an immune response (e.g., to treat or prevent infection), or POP1 and/or POP3 are administered or activated to reduce an immune response (e.g., to treat or prevent autoimmune or inflammatory disease).