Abstract
Lymphopenic conditions lead to expansion of memory-like T cells (TML), which develop from naïve T cells by spontaneous proliferation. TML cells are often increased in the elderly population, AIDS patients, and patients recovering from radio- or chemotherapy. At present, it is unclear whether TML cells can efficiently respond to foreign antigen and participate in antiviral immunity. To address this question, we analyzed the immune response during acute low-dose infection with lymphocytic choriomeningitis virus-WE in T cell lymphopenic CD4Cre/R-diphtheria toxin alpha (DTA) mice in which most peripheral T cells show a TML phenotype. On day 8 after infection, the total number of effector T cells and polyfunctional IFN-γ and TNF-α producing CD8 T cells were three- to fivefold reduced in CD4Cre/R-DTA mice as compared to controls. Viral clearance and the humoral immune response were severely impaired in CD4Cre/R-DTA mice although CTLs efficiently killed transferred target cells in vivo. Transfer of naïve CD4 T cells but not anti-PD-L1 blockade restored the expansion of antigen-specific polyfunctional CD8 T cells and resulted in lower viral titers. This finding indicates that under lymphopenic conditions endogenous CD4 TML cell lack the capacity to promote expansion of CTLs. However, CD8 TML cells retain sufficient functional plasticity to participate in antiviral immunity in the presence of appropriate help by fully functional CD4 T cells. This capacity might be exploited to develop treatments for improvement of CD8 T cell functions under various clinical settings of lymphopenia.
Highlights
T cell homeostasis is regulated by thymic output as well as proliferation and death of peripheral T cells [1]
Expression of diphtheria toxin alpha (DTA) in developing T cells of CD4Cre+R-DTA− control mice (CD4Cre)/R-DTA mice leads to almost complete deletion of naïve peripheral T cells despite normal numbers of T cells with a memory phenotype (TMP) [(22); Figure 1A]
Using constitutively T cell-lymphopenic CD4Cre/R-DTA mice we demonstrate here that CTLs developed from CD8 TML cells and efficiently killed transferred target cells but could not control viral replication during low-dose acute lymphocytic choriomeningitis virus (LCMV) infection
Summary
T cell homeostasis is regulated by thymic output as well as proliferation and death of peripheral T cells [1]. Naïve T cells require recognition of cognate MHC and cytokines like IL-7 or IL-15 for survival. The pool of TMP cells consists of real antigen-experienced TM and memory-like T cells (TML) that converted from naïve T cells by spontaneous proliferation under lymphopenic conditions [lymphopenia-induced proliferation (LIP)] [4, 5]. Increased numbers of TML cells are believed to make a substantial contribution to the TMP pool in AIDS patients or patients recovering from radio- or chemotherapy. It remains unclear whether TML cells can be engaged in mounting a primary immune response. TML cells may further compete with real TM for survival, which could lead to attrition of the TM pool under lymphopenic conditions [6,7,8]
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