Thymic expression of IL-4 and IL-15 after systemic inflammatory or infectious Th1 disease processes induce the acquisition of "innate" characteristics during CD8+ T cell development

Abstract

Innate CD8+ T cells express a memory-like phenotype and demonstrate a strong cytotoxic capacity that is critical during the early phase of the host response to certain bacterial and viral infections. These cells arise in the thymus and depend on IL-4 and IL-15 for their development. Even though innate CD8+ T cells exist in the thymus of WT mice in low numbers, they are highly enriched in KO mice that lack certain kinases, leading to an increase in IL-4 production by thymic NKT cells. Our work describes that in C57BL/6 WT mice undergoing a Th1 biased infectious disease, the thymus experiences an enrichment of single positive CD8 (SP8) thymocytes that share all the established phenotypical and functional characteristics of innate CD8+ T cells. Moreover, through in vivo experiments, we demonstrate a significant increase in survival and a lower parasitemia in mice adoptively transferred with SP8 thymocytes from OT I—T. cruzi-infected mice, demonstrating that innate CD8+ thymocytes are able to protect against a lethal T. cruzi infection in an Ag-independent manner. Interestingly, we obtained similar results when using thymocytes from systemic IL-12 + IL-18-treated mice. This data indicates that cytokines triggered during the acute stage of a Th1 infectious process induce thymic production of IL-4 along with IL-15 expression resulting in an adequate niche for development of innate CD8+ T cells as early as the double positive (DP) stage. Our data demonstrate that the thymus can sense systemic inflammatory situations and alter its conventional CD8 developmental pathway when a rapid innate immune response is required to control different types of pathogens.

Induced Prostanoid Synthesis Regulates the Balance between Th1- and Th2-Producing Inflammatory Cytokines in the Thymus of Diet-Restricted Mice

“…40) Recent studies have indicated that IL-4 in the thymus inhibits the commitment of early thymic progenitor cells to T cell lineage as well as the differentiation of CD8 + cytotoxic T cells. 41,42) IL-4 expression in the thymus may be strictly controlled to avoid its unpleasant effect on T cell development.…”

Innate T-αβ lymphocytes as new immunological components of anti-tumoral “off-target” effects of the tyrosine kinase inhibitor dasatinib

“…Thus, we could not rule out the involvement of cytokines other than IL-4 to sustain T TM cells. In this regard, it was recently shown in a systemic inflammatory mouse model induced by IL-12+IL-18 systemic production that innate CD8 T-cell development depends on both IL-4, IL-15 and IFNγ 44 .…”

The Thymus in Chagas Disease: Molecular Interactions Involved in Abnormal T-Cell Migration and Differentiation

“…In keeping with this hypothesis, some studies indicate that the parasite-derived enzyme trans-sialidase may be involved in the thymic atrophy ( 83 , 84 ). Despite that T. cruzi can infect the thymus ( 43 , 46 , 58 ) and release locally antigens, some studies have shown that when trans-sialidase is artificially shed to circulation, it induces thymocyte apoptosis ( 85 ). Moreover, mice treated with trans-sialidase displayed enhanced thymocyte apoptosis within the thymic nurse cell complexes, findings resembling thymic alterations in infected animals ( 83 ).…”

“…In addition, recent work showed that Th1 systemic response against T. cruzi is able to influence the intrathymic development of a particular population among CD8 + SP thymocytes: the “CD8 + innate cells or innate memory–phenotype” (T IM -CD8 + ) cells ( 43 ). As mentioned in Box 1 , these subpopulation is generated as an independent lineage different from conventional CD8 + T cells ( 25 , 26 , 121 ).…”