Abstract
Naïve antigen-specific CD8 T cells expand in response to infection and can be phenotypically separated into distinct effector populations, which include memory precursor effector cells (MPECs) and short-lived effector cells (SLECs). In the days before the peak of the T cell response, a third population called early effector cells (EECs) predominate the antigen-specific response. However, the contribution of the EEC population to the CD8 T cell differentiation program during an antimicrobial immune response is not well understood. To test if EEC populations were pre-committed to either an MPEC or SLEC fate, we purified EECs from mice infected with Listeria monocytogenes (LM) or vesicular stomatitis virus (VSV), where the relative frequency of each population is known to be different at the peak of the response. Sorted EECs transferred into uninfected hosts revealed that EECs were pre-programmed to differentiate based on early signals received from the distinct infectious environments. Surprisingly, when these same EECs were transferred early into mismatched infected hosts, the transferred EECs could be diverted from their original fate. These results delineate a model of differentiation where EECs are programmed to form MPECs or SLECs, but remain susceptible to additional inflammatory stimuli that can alter their fate.
Highlights
Cytotoxic CD8 T cells play an important role in controlling intracellular infections through recognition of antigenic peptides presented on MHC class I molecules
Using the lack of CD127 and killer-cell lectin-like receptor G1 (KLRG1) expression to identify effector cells (EECs), our results indicated that the frequency of EECs present at the peak of the immune response was different in the spleens of mice infected with Listeria monocytogenes (LM) versus vesicular stomatitis virus (VSV) (Fig. 1A)
We found that LM EECs transferred into uninfected mice and left for an additional 3 or 6 days differentiated into short-lived effector cells (SLECs) and memory precursor effector cells (MPECs) (Fig. 2B), which suggested that EECs are a source of downstream MPEC and SLEC populations
Summary
Cytotoxic CD8 T cells play an important role in controlling intracellular infections through recognition of antigenic peptides presented on MHC class I molecules. Our lab previously phenotyped CD8 T cells prior to the peak of the immune response (2–5 days post-infection) and showed that the majority of cells lack expression of both CD127 and KLRG1 (CD127-KLRG1-) at this time[10] This population has the capacity to give rise to both SLECs and MPECs. This population has the capacity to give rise to both SLECs and MPECs These early effector cells (EECs) are so named because on par with SLECs and MPECs, they express the effector molecules granzyme B and IFN-γ early after infection[4]. We have previously identified cytokines and transcription factors that regulate the differentiation of antigen specific CD8 T cell differentiation into SLEC and MPEC10, it remains unclear how stable these differentiation events are and how early these events are predetermined While both SLECs and MPECs arise from the EEC population, it remains unclear if commitment towards a SLEC versus MPEC fate occurs as cells transition through the EEC phase. These results suggest that EECs are imprinted during priming but still retain plasticity to respond to specific external inflammatory cues that are induced by the type of invading pathogen
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