Inborn Errors of T Cell Topographic Memory Underlie Organ-Selective Infectious Diseases

Background and Aim Most infections are innocuous in most individuals, and most infectious diseases are confined to specific organs. Inborn errors of tissue-intrinsic, non-leukocytic immunity underlie some organ-specific infectious diseases, but most severe infections remain unexplained. We hypothesize that inherited “lacunar” defects of tissue-homing memory T cells can underlie organ-selective infections. Methods We screened >20,000 genomes from patients with severe, unexplained organ-specific infections for candidate variants potentially affecting T cell trafficking. We then performed extensive functional studies to validate disease-causing mutations and define their impact on memory T cell compartmentalization and local immune surveillance. Results We identified autosomal recessive deficiency of integrin αL (CD11a), due to biallelic loss-of-function mutations in ITGAL, in otherwise healthy adults of various ancestries with severe, persistent cutaneous lesions due to commensal papillomaviruses. The absence of CD11a does not compromise the development or function of any leukocyte subset, including CD4+ helper and CD8+ cytotoxic T cells. However, the trafficking of skin-tropic memory T cells is severely impaired, resulting in their selective sequestration in the blood and compromising the establishment of tissue-resident memory T cells in the skin. Conversely, alternative integrins mediate the extravasation of other leukocytes, including other T cell subsets, to other tissues. This leads to a skin-restricted T cell immunodeficiency characterized by the expansion of the commensal viral flora, including β-HPV, and a predisposition to skin cancers. Conclusion Human integrin αL is essential for steady-state T cell homing to the skin but largely redundant for protective immunity in other tissues. Our study provides proof of concept that severe organ-selective viral diseases can result from lacunar defects in tissue-specific memory T cell homing in patients whose immunity is otherwise intact.