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1 Deficiency1
* Department of Pediatrics and the Immunology Program, Stanford University School of Medicine, Stanford, CA 94305; and
DNAX Research Institute, Palo Alto, CA 94304
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-12R
1-chain gene. This
mutation resulted in the absence of IL-12R1 protein on PBMC and an
inability of T cells to specifically bind IL-12 or produce IFN-
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-
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- after polyclonal stimulation. Importantly,
tetanus toxoid-specific IFN- production by PBMC from the patient was
also significantly reduced compared with that in age-matched controls,
indicating that signaling via the IL-12R1-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-12R1 subunit is necessary for the conversion of central
memory CD4 T cells into effector memory cells.
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