Type 1 IFN Maintains the Survival of Anergic CD4+ T Cells

Abstract

Anergic T cells have immunoregulatory activity and can survive for extended periods in vivo. It is unclear how anergic T cells escape from deletion, because both anergy and apoptosis can occur after TCR ligation. Stimulation of human CD4+ T cell clones reactive to influenza hemagglutinin peptides can occur in the absence of APCs when MHC class II-expressing, activated T cells present peptide to each other. This T:T peptide presentation can induce CD95-mediated apoptosis, while the cells that do not die are anergic. We found that the death after peptide or anti-CD3 treatment of a panel of CD4+ T cell clones is blocked by IFN-β secreted by fibroblasts and also by IFN-α. This increases cell recovery after stimulation, which is not due to T cell proliferation. This mechanism for apoptosis inhibition rapidly stops protein kinase C-δ translocation from the cytoplasm to the nucleus, which is an early event in the death process. A central observation was that CD4+ T cells that are rescued from apoptosis after T:T presentation of peptide by IFN-αβ remain profoundly anergic to rechallenge with Ag-pulsed APCs. However, anergized cells retain the ability to respond to IL-2, showing that they are nonresponsive but functional. The prevention of peptide-induced apoptosis in activated T cells by IFN-αβ is a novel mechanism that may enable the survival and maintenance of anergic T cell populations after TCR engagement. This has important implications for the persistence of anergic T cells with the potential for immunoregulatory function in vivo.

STAT1 Signaling in CD8 T Cells Is Required for Their Clonal Expansion and Memory Formation Following Viral Infection In Vivo

“…Our observation that the diminished clonal expansion of CD8 T cells that lack STAT1 signaling is due to their poor survival following activation in vivo is in line with previous studies that report activated T cells survive better in the presence of type I IFNs (27,28). Furthermore, STAT1-deficient effector CD8 T cells could not survive the contraction phase to develop into long-lived memory CD8 T cells.…”

Interferon-β

“…Whereas Rep et al (35) report that IFN-␤ inhibits the proliferation of T cells and reduces the secretion of IFN-␥ and TNF-␣ depending on the dose in patients with multiple sclerosis, Zipp et al (36) detected no evidence of apoptosis induction by IFN-␤ on myelin specific autoreactive T cells. Moreover, even a protective effect of IFN-␤ on T cells was described (37)(38)(39). Similarly, in the MRL-Fas lpr mouse model, IFN-␤ seems to counteract IFN-␥-induced TEC death (unpublished observation).…”

Intestinal Fibroblast-Derived IL-10 Increases Survival of Mucosal T Cells by Inhibiting Growth Factor Deprivation- and Fas-Mediated Apoptosis

“…In contrast to IL-2, but similarly to rIL-10 and IFN-␤, FCM from untransfected HIF, and FCM from HIF transfected with scrambled DNA, IL-10 or IFN-␤ antisense oligonucleotides failed to induce mucosal T cell proliferation. This suggests that HIF-derived IL-10 maintains survival of mature T cell in a quiescent state like type I IFNs do (55,56). This property is particularly important in the intestine because it may prevent T cell activation in the highly stimulatory environment of the intestinal mucosa.…”

“…Having excluded PGE 2 as a major antiapoptotic factor in FCM, we next investigated IFN-␤ because this cytokine has been shown to be involved in the rescue of T cell apoptosis in various experimental and clinical systems (29,48,55,56). Although IFN-␤ mRNA was present in HIF extracts, the protein was not detected in cultures of HIF unstimulated or HIF activated by IL-1␤, whereas both IL-10 and PGE 2 were detected and significantly up-regulated in the same cultures.…”