Abstract
The fast and intense proliferative responses have been well documented for naïve T cells adoptively transferred into chronic lymphopenic hosts. This response known as spontaneous proliferation (SP), unlike antigen-independent lymphopenia-induced proliferation (LIP), is driven in a manner dependent on antigens derived from commensal microbiota. However, the precise nature of the SP response and its impact on homeostasis and function for T cells rapidly responding under this lymphopenic condition are still unclear. Here we demonstrate that, when naïve T cells were adoptively transferred into specific pathogen-free (SPF) but not germ-free (GF) RAG−/− hosts, the SP response of these cells substantially affects the intensity and tempo of the responding T cells undergoing LIP. Therefore, the resulting response of these cells in SPF RAG−/− hosts was faster and stronger than the typical LIP response observed in irradiated B6 hosts. Although the intensity and tempo of such augmented LIP in SPF RAG−/− hosts were analogous to those of antigen-dependent SP, the former was independent of antigenic stimulation but most importantly, dependent on IL-2. Similar observations were also apparent in other acute lymphopenic settings where antigen-dependent T cell activation can strongly occur and induce sufficient levels of IL-2 production. Consequently, the resulting T cells undergoing IL-2-driven strong proliferative responses showed the ability to differentiate into functional effector and memory cells that can control infectious pathogens. These findings therefore reveal previously unappreciated role of IL-2 in driving the intense form of T cell proliferative responses in chronic lymphopenic hosts.
Highlights
Proliferation of naïve T cells under lymphopenic environments has long been accepted as a crucial homeostatic mechanism by which a diverse repertoire of these cells can be stably maintained at constant number during their peripheral life-time [1, 2]
Cells transferred into specific pathogen-free (SPF) RAG−/− hosts showed robust proliferative responses, as evidenced by the full dilution of CTV dye; these responses were abrogated substantially in GF RAG−/− hosts, confirming the previous findings showing stringent dependence of the spontaneous proliferation (SP) responses of polyclonal naïve CD4+ T cells on antigens derived from commensal microbiota [15]
The recovery of donor cells was ∼10-20-fold lower for the lymphopenia-induced homeostatic proliferation (LIP) responses in GF RAG−/− and irradiated B6 hosts than those for the SP responses observed in SPF RAG−/− hosts (Figure 1A, right)
Summary
Proliferation of naïve T cells under lymphopenic environments has long been accepted as a crucial homeostatic mechanism by which a diverse repertoire of these cells can be stably maintained at constant number during their peripheral life-time [1, 2] This proliferative response, known as lymphopenia-induced homeostatic proliferation (LIP), is considered as a common phenomenon for the most polyclonal and even monoclonal naïve T cell repertoire adoptively transferred into a recipient animal under various lymphodepletion settings either genetically (e.g., RAG−/−, TCRβ−/−, CD3ε−/−, and SCID mice) or conditionally How the commensal antigens are presented to stimulate the SP response of T cells in these hosts and if so, why this phenomenon fails to occur in other lymphopenic hosts, such as irradiated C57BL/6 (B6) mice, remains to be addressed
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