(A) Sirolimus, an mTOR inhibitor, is effective in children with m-IC syndromes, improving and/or eliminating abnormal lymphocyte populations that drive immune dysregulation, including cTfh and decreasing markers of abnormal T-cell activation, senescence, and exhaustion on CD4⁺ and CD8⁺ effector memory T cells, along with a reduction of Th1 polarization. Ultimately, sirolimus improved disease manifestations without leading to immune deficiency. Panel B depicts targeted therapies currently available to treat children and adults with different monogenic causes of m-IC. Similar studies evaluating the mechanism of action and short- and long-term impacts on immune health are needed. ADA2, adenosine deaminase deficiency 2; ALPS, autoimmune lymphoproliferative syndrome; CHAI, CTLA4 haploinsufficiency with autoimmune infiltration; Evans, syndrome characterized by m-ICs without known cause; GOF, gain of function; IFN, interferon; IPEX, immune dysregulation polyendocrinopathy, enteropathy, X-linked; LATAIE, LRBA deficiency with autoantibodies, regulatory T (Treg) cell defects, autoimmune infiltration, and enteropathy; MMF, mycophenolate mofetil; PASLI, p110d-activation with senescent T cells, lymphadenopathy, and immunodeficiency; PRKCD, protein kinase C delta deficiency; RALD, ras-associated leukoproliferative disease; TNF, tumor necrosis factor; TNFAIP3, tumor necrosis factor alpha infused protein 3.