Abstract
CD4 T cells in human infants and adults differ in the initiation and strength of their responses. The molecular basis for these differences is not yet understood. To address this the principle key molecular events of TCR- and CD28-induced signaling in naive CD4 T cells, such as Ca2+ influx, NFAT expression, phosphorylation and translocation into the nucleus, ERK activation and IL-2 response, were analyzed over at least the first 3 years of life. We report dramatically reduced IL-2 and TNFα responses in naive CD31+ T cells during infancy. Looking at the obligatory Ca2+ influx required to induce T cell activation and proliferation, we demonstrate characteristic patterns of impairment for each stage of infancy that are partly due to the differential usage of Ca2+ stores. Consistent with those findings, translocation of NFATc2 is limited, but still dependent on Ca2+ influx as demonstrated by sensitivity to cyclosporin A (CsA) treatment. Thus weak Ca2+ influx functions as a catalyst for the implementation of restricted IL-2 response in T cells during infancy. Our studies also define limited mobilization of Ca2+ ions as a characteristic property of T cells during infancy. This work adds to our understanding of infants’ poor T cell responsiveness against pathogens.
Highlights
The mammalian adaptive immune system provides specific and long-lasting protection against pathogens
No CD28 enhanced Ca2+ influx comparable to that seen in adults was detected in cord blood (CB) and infants, including the youngest ones of 1–2 and 3–5 months
Our findings represent the first observations of distinct T cell receptor (TCR) and/or CD28 engagement effects on the activation of early signaling pathways in naive T cells during the first 66 months of life compared to the effects seen in adult recent thymic emigrants (RTE) T cells
Summary
The mammalian adaptive immune system provides specific and long-lasting protection against pathogens. The adaptive immune system must learn to tolerate innocuous antigens from the environment. In this challenging time period for the immune system, epidemiological studies have shown that neonates and infants are especially susceptible to infections; this period of life is decisive for directing immune responses and pathologies later in life [1]. T cell functions, such as cytokine production, are downregulated in response to antigens of acute infections during the neonatal and early infancy periods [2,3]. This has been attributed to reduced numbers of neonatal
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