Fidelity of Pathogen-Specific CD4+ T Cells to the Th1 Lineage Is Controlled by Exogenous Cytokines, Interferon-γ Expression, and Pathogen Lifestyle

Abstract

SUMMARY The degree of lineage stability achieved by pathogen-specific CD4+ T cells in vivo, and how this impacts host defense against infection, remains unclear. We demonstrate that in response to Th1-polarizing intracellular bacterial or viral pathogens, only 80–90% of responding polyclonal T cells become indelibly committed to this lineage. Th1 commitment was nearly invariant in cells that proliferated extensively, but perturbations to the extrinsic cytokine milieu or the pathogen’s ability to enter the cytosol impeded commitment and promoted plasticity for future IL-17 expression. Conversely, cell intrinsic interferon-γ expression and acquisition of permissive chromatin at the Ifng gene during priming predicted heritable Th1 commitment. Importantly, CD4+ T cells that retained plasticity conferred protection against M. tuberculosis, while these protective effects were abolished with Th17 polarization. These findings illustrate the immune signals that induce memory CD4+ T cell responses required for maintaining host defense against infection yet are adaptable in novel environmental contexts.

Cutting Edge: Committed Th1 CD4+ T Cell Differentiation Blocks Pregnancy-Induced Foxp3 Expression with Antigen-Specific Fetal Loss

“…We previously described Lm cytoplasmic entry primes Th1 CD4 + T cell polarization and differentiation stability for cells responsive to Lm expressed antigen (23). However, the use of monoclonal cells from TCR transgenic mice with fixed specificity may limit their applicability for Treg differentiation given the discordance in affinity and TCR repertories between Foxp3 + and Foxp3 - CD4 + T cells (27).…”

“…Given the sharp discordance in Treg differentiation between Lm infection and fetal stimulation, we reasoned committed Th1 differentiation by recombinant Lm could be exploited to investigate the necessity for Foxp3 induction among maternal CD4 + T cells during pregnancy. As controls for infection and 2W1S 55-68 stimulation, CD4 + T cells primed by Lm restricted from the cell cytoplasm due to combined defects in Listeriolysin-O (LLO) and phospholipase-C (PLC) (ΔLLOΔPLC Lm) with increased plasticity for differentiation into other effector lineages were evaluated in parallel (23, 25). …”

“…For infection, Lm were grown to early log-phase (OD 600 0.1), washed and suspended in PBS and inoculated i.v. at the following dosages: ΔACTA Lm-2W1S (10 6 CFUs), ΔLLOΔPLC Lm-2W1S (10 7 CFUs), or non-recombinant ΔACTA Lm (10 6 CFUs) (23-25). For adoptive transfer, CD4 + T cells from the spleen and lymph nodes were purified by negative selection, and one mouse equivalent of CD45.1 + and CD90.1 + cells at an 1:1 ratio were inoculated i.v.…”

Toll-Like Receptor 2-Dependent Extracellular Signal-Regulated Kinase Signaling in Mycobacterium tuberculosis-Infected Macrophages Drives Anti-Inflammatory Responses and Inhibits Th1 Polarization of Responding T Cells

“…T helper type 1 (Th1) responses and the production of interferon gamma (IFN-␥) are particularly important to the containment of M. tuberculosis infection (4-6), but T cells exhibit delayed responses in the lung and do not provide sterilizing immunity (7)(8)(9)(10). Effector T cells may exhibit plasticity in their Th1 polarization due to effects of the lung microenvironment (11)(12)(13).…”

Antigen Signal Strength during Priming Determines Effector CD4 T Cell Function and Antigen Sensitivity during Influenza Virus Challenge

“…Dominant epitope-specific CD4 T cells become terminally differentiated upon bacterial challenge while cryptic epitope-specific T cells enhanced IL-17A production. These results suggest that effector Th1 cells elicited by suboptimal TCR stimulation (lower stability peptides, cryptic epitopes) exhibit considerable plasticity for future IL-17 expression (46–48), perhaps due decreased exposure to Th1 polarizing cytokines (49). …”