Cytokine Diversity in the Th1-Dominated Human Anti-Influenza Response Caused by Variable Cytokine Expression by Th1 Cells, and a Minor Population of Uncommitted IL-2+IFNγ- Thpp Cells

Abstract

Within overall Th1-like human memory T cell responses, individual T cells may express only some of the characteristic Th1 cytokines when reactivated. In the Th1-oriented memory response to influenza, we have tested the contributions of two potential mechanisms for this diversity: variable expression of cytokines by a uniform population during activation, or different stable subsets that consistently expressed subsets of the Th1 cytokine pattern. To test for short-term variability, in vitro-stimulated influenza-specific human memory CD4+ T cells were sorted according to IL-2 and IFNγ expression, cultured briefly in vitro, and cytokine patterns measured after restimulation. Cells that were initially IFNγ+ and either IL-2+ or IL-2- converged rapidly, containing similar proportions of IL-2-IFNγ+ and IL-2+IFNγ+ cells after culture and restimulation. Both phenotypes expressed Tbet, and similar patterns of mRNA. Thus variability of IL-2 expression in IFNγ+ cells appeared to be regulated more by short-term variability than by stable differentiated subsets. In contrast, heterogeneous expression of IFNγ in IL-2+ influenza-specific T cells appeared to be due partly to stable T cell subsets. After sorting, culture and restimulation, influenza-specific IL-2+IFNγ- and IL-2+IFNγ+ cells maintained significantly biased ratios of IFNγ+ and IFNγ- cells. IL-2+IFNγ- cells included both Tbetlo and Tbethi cells, and showed more mRNA expression differences with either of the IFNγ+ populations. To test whether IL-2+IFNγ-Tbetlo cells were Thpp cells (primed but uncommitted memory cells, predominant in responses to protein vaccines), influenza-specific IL-2+IFNγ- and IL-2+IFNγ+ T cells were sorted and cultured in Th1- or Th2-generating conditions. Both cell types yielded IFNγ-secreting cells in Th1 conditions, but only IL-2+IFNγ- cells were able to differentiate into IL-4-producing cells. Thus expression of IL-2 in the anti-influenza response may be regulated mainly by short term variability, whereas different T cell subsets, Th1 and Thpp, may contribute to variability in IFNγ expression.

Neurotoxin from Naja naja atra venom inhibits skin allograft rejection in rats

“…The Th1 cells produce IL-2, IFN-γ, TNF, etc., while the Th2 cells produce IL-4, IL-5, IL-6, IL-10, etc. During allograft rejection, Th1 cytokine (IL-2, IFN-γ) production was increased, while Th2 cytokines (IL-4, IL-10) were secreted at a low level or even absent [44,45]. In our rat skin allograft model, the expression of IL-2 and IFN-γ was markedly enhanced, either mid-course in the rejection progress or after loss of the skin allografts.…”

A Structural and Mathematical Modeling Analysis of the Likelihood of Antibody-Dependent Enhancement in Influenza

“…Indeed, Th2 polarization of the immune response in RSV infection is a hallmark of more severe disease[43] and several viral gene products, including soluble G protein, promote such a response[67]. This is in contrast to influenza infection, where influenza immunity is largely driven by a Th1 response[68], with the virus suppressing efficient recruitment of Th2 cells[69]. Thus, while such an immune-modulating mechanism appears to be the case for RSV, and potentially other viruses, no information suggests that this is true for influenza.…”

An animated landscape representation of CD4+ T‐cell differentiation, variability, and plasticity: Insights into the behavior of populations versus cells

“…A more dichotomous example of this type of diversity is the well‐known variable expression of several cytokine genes, both at the level of on/off expression, for example, Th1 cells may be IL‐2 + IFN‐γ + , IL‐2 + IFN‐γ − , IL‐2 − IFN‐γ + , or IL‐2 − IFN‐γ − during any single stimulation cycle , and also in mono‐ and diallelic expression patterns . These two phenomena may be linked, as stochastic expression of individual alleles would predict a mixture of positive and negative cells.…”

“…This animation mimics naïve T cells differentiating to Th1 or Th2 effector states, but includes several semistable intermediate states. These could include the uncommitted Thpp and Tbet + GATA3 + differentiation states that can both be intermediates on the Th1 and Th2 differentiation pathways.…”

“…Th1 cells may express IL‐2 in an apparently random pattern, whereas IFN‐γ expression shows more continuity (“memory” for the previous state) . This may be due to different kinetics of randomization.…”