Impaired Accumulation and Function of Memory CD4 T Cells in Human IL-12 Receptor β1 Deficiency

• Published in: The Journal of immunology (1950) 2003-01, Vol.170 (1), p.597-603
• Main Authors: Cleary, Aileen M., Tu, Wenwei, Enright, Andrea, Giffon, Thierry, Dewaal-Malefyt, Rene, Gutierrez, Kathleen, Lewis, David B.
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.170.1.597

Defects in IL-12 production or IL-12 responsiveness result in a vulnerability to infection with non-viral intracellular organisms, but the immunological mechanisms responsible for this susceptibility remain poorly understood. We present an immunological analysis of a patient with disseminated Salmonella enteritidis and a homozygous splice acceptor mutation in the IL-12Rβ1-chain gene. This mutation resulted in the absence of IL-12Rβ1 protein on PBMC and an inability of T cells to specifically bind IL-12 or produce IFN-γ in response to either IL-12 or IL-23. The accumulation of memory (CD45R0high) CD4 T cells that were CCR7high (putative central memory cells) was normal or increased for age. Central memory CD4 T cells of the patient and age-matched controls were similar in having a low to undetectable capacity to produce IFN-γ after polyclonal stimulation. In contrast, the patient had a substantial decrease in the number of CCR7neg/dull CD45R0high memory CD4 T cells (putative effector memory cells), and these differed from control cells in having a minimal ability to produce IFN-γ after polyclonal stimulation. Importantly, tetanus toxoid-specific IFN-γ production by PBMC from the patient was also significantly reduced compared with that in age-matched controls, indicating that signaling via the IL-12Rβ1-chain is generally necessary for the in vivo accumulation of human memory CD4 T cells with Th1 function. These results are also consistent with a model in which the IL-12Rβ1 subunit is necessary for the conversion of central memory CD4 T cells into effector memory cells.