Inherited human PD-1 deficiency underlies tuberculosis and autoimmunity
Abstract The pathogenesis of adverse reactions to PD-1 blockade immunotherapy, including tuberculosis (TB) and autoimmunity, remains poorly characterized. Here, we study a patient with inherited PD-1 deficiency who suffered from TB and died of pulmonary autoimmunity. The patient’s leukocytes display...
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Published in | The Journal of immunology (1950) Vol. 206; no. 1_Supplement; pp. 52 - 52.10 |
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Main Authors | , , , , |
Format | Journal Article |
Language | English |
Published |
01.05.2021
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Online Access | Get full text |
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Summary: | Abstract
The pathogenesis of adverse reactions to PD-1 blockade immunotherapy, including tuberculosis (TB) and autoimmunity, remains poorly characterized. Here, we study a patient with inherited PD-1 deficiency who suffered from TB and died of pulmonary autoimmunity. The patient’s leukocytes displayed no PD-1 expression and did not respond to PD-1-mediated suppression. Similar to various inborn errors of immunity impairing interferon (IFN)-γ production and underlying TB, the patient’s lymphocytes poorly produced IFN-γ in response to mycobacterial stimuli owing to both the depletion of multiple IFN-γ-producing T and NK lymphocyte subsets, including Vδ2+ γδ T, MAIT, and CD56bright NK lymphocytes, and dysfunction of residual T lymphocytes. Another set of inborn errors, including STAT3 gain-of-function (GOF) mutations, trigger an expansion of CD4−CD8− double-negative (DN) αβ T cells and underlie lymphoproliferative autoimmunity. Remarkably, the patient displayed hepatosplenomegaly and expansion of total, activated, and RORγT+ DN αβ T cells, as observed in PD-1-deficient mice and cancer patients with PD-1 blockade. Mechanistically, the patient’s myeloid cells produced excessive amounts of STAT3-activating cytokines IL-6 and IL-23 upon stimulation with lipopolysaccharide. Overall, inherited human PD-1 deficiency underlies TB through undermining IFN-γ production by T and NK lymphocytes and lymphoproliferative autoimmunity through over-activating STAT3. |
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ISSN: | 0022-1767 1550-6606 |
DOI: | 10.4049/jimmunol.206.Supp.52.10 |