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

Abstract

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.

Persistent and Selective Deficiency of CD4+ T Cell Immunity to Cytomegalovirus in Immunocompetent Young Children

“…2). These findings are in agreement with two earlier studies (25,26) in which the CCR7 low subset of memory CD4 ϩ T cells was observed to contain almost all IFN-␥-producing cells among CD4 ϩ T cells polyclonally activated using CD3 and CD28 mAbs. In one of these studies (26), the production of IL-4 by memory CD4 ϩ T cells was also largely restricted to the CCR7 low rather than the CCR7 high subset.…”

“…This modest reduction could reflect a general tendency of young children to produce fewer CCR7 low cells to antigenic stimuli, although this remains to be shown. Consistent with this idea is the recent finding that circulating monocytes from healthy infants and young children have a reduced capacity to produce IL-12 (36), a cytokine that is required for the accumulation of CCR7 low memory CD4 ϩ T cells with Th1 function (25). Although speculative, it is also plausible that the increased proportion of CCR7 low memory CD4 ϩ T cells in adults could reflect their greater cumulative exposure to natural infections that are effective at driving Th1 immune responses compared with the young children of our study, for whom a greater proportion of antigenic stimulation may be derived from vaccines that are relatively ineffective Th1 inducers.…”

“…CMV can also directly infect human myeloid dendritic cells (48,49), which are key APCs for the initiation of the adaptive immune response and in directing CD4 ϩ T cell differentiation toward Th1 effector function or other fates (50). Such infection may interfere with the ability of dendritic cells to present Ags to CD4 ϩ T cells (48) and produce IL-12 (49), a key cytokine for the generation of Th1 cells in humans (25). These and other potential mechanisms, such as blockade by CMV infection of IFN-␥-mediated intracellular signaling and downstream up-regulation of molecules involved in Ag presentation (51), could inhibit the generation of Th1 responses in vivo.…”

“…We verified that this applied to CMV-specific and SEB-induced IFN-␥ production by CD4 ϩ T cells from adults with presumed chronic CMV infection or adults and children with documented recent primary infection (data not shown). Because memory CD4 ϩ T cells expressing low levels of CCR7 have been reported to be highly enriched in IFN-␥ production after engagement of CD3 and CD28 (25,26), we next determined whether this restriction of Th1 function to CCR7 low memory cells also applied to CMV Ag-specific responses. Among adult and child memory CD4 ϩ T cells, Ͼ90% of cells that produced IFN-␥ in response to either stimulation with CMV Ag, the pp65 peptide mixture, or SEB were CCR7 low (Fig.…”

“…It has been reported that IFN-␥ production by adult CD4 ϩ T cells in response to protein Ag (22)(23)(24), including CMV (18) or SEB (25), is largely confined to CD45RA low CD45R0 high memory/effector subset. We verified that this applied to CMV-specific and SEB-induced IFN-␥ production by CD4 ϩ T cells from adults with presumed chronic CMV infection or adults and children with documented recent primary infection (data not shown).…”