Which form of severe combined immunodeficiency is caused by a defective interleukin-2 receptor gamma chain leading to markedly reduced T, B, and natural killer cells?

• A. ADA deficiency SCID
• B. JAK3 deficiency
• C. X-linked SCID (IL2RG deficiency)
• D. RAG1 deficiency

Answer: (C)

Defective interleukin-2 receptor gamma chain blocks signaling for several cytokines that drive lymphocyte development, especially IL-7 for T cells and IL-15 for natural killer (NK) cells. Without this common gamma chain functioning, thymic T cell production collapses and NK cell development is severely impaired, leading to very low T and NK cell numbers. B cells are present but cannot be effectively helped by T cells, so antibody responses are poor. This specific defect defines X-linked SCID due to IL2RG deficiency, which explains the markedly reduced T, B, and NK cells seen clinically. While other forms of SCID exist, such as ADA deficiency or RAG1 deficiency, they involve different mechanisms—ADA deficiency causes toxic metabolite buildup affecting multiple lymphocyte lineages, and RAG1 deficiency blocks V(D)J recombination, mainly impacting T and B cells with NK cells typically preserved. JAK3 deficiency can resemble X-linked SCID in phenotype but is autosomal recessive and affects downstream signaling rather than the gamma chain itself.