Protein Vaccines Induce Uncommitted IL-2-Secreting Human and Mouse CD4 T Cells, Whereas Infections Induce More IFN-γ-Secreting Cells

Abstract

Mouse and human CD4 T cells primed during an immune response may differentiate into effector phenotypes such as Th1 (secreting IFN-γ) or Th2 (secreting IL-4) that mediate effective immunity against different classes of pathogen. However, primed CD4 T cells can also remain uncommitted, secreting IL-2 and chemokines, but not IFN-γ or IL-4. We now show that human CD4 T cells primed by protein vaccines mostly secreted IL-2, but not IFN-γ, whereas in the same individuals most CD4 T cells initially primed by infection with live pathogens secreted IFN-γ. We further demonstrate that many tetanus-specific IL-2+IFN-γ− cells are uncommitted and that a single IL-2+IFN-γ− cell can differentiate into Th1 or Th2 phenotypes following in vitro stimulation under appropriate polarizing conditions. In contrast, influenza-specific IL-2+IFN-γ− CD4 cells maintained a Th1-like phenotype even under Th2-polarizing conditions. Similarly, adoptively transferred OTII transgenic mouse T cells secreted mainly IL-2 after priming with OVA in alum, but were biased toward IFN-γ secretion when primed with the same OVA peptide presented as a pathogen Ag during live infection. Thus, protein subunit vaccines may prime a unique subset of differentiated, but uncommitted CD4 T cells that lack some of the functional properties of committed effectors induced by infection. This has implications for the design of more effective vaccines against pathogens requiring strong CD4 effector T cell responses.

Antigen-Specific Central Memory CD4+ T Lymphocytes Produce Multiple Cytokines and Proliferate In Vivo in Humans

“…The high proportion of IL-2-producing CD4 ϩ T cells detected following HBVac immunization is in accordance with data reported recently indicating that protein vaccines induce uncommitted IL-2-secreting CD4 ϩ T cells, whereas infections induce more IFN-␥-secreting cells (28,29). However, the large proportions of TNF-␣-secreting cells observed following HBVac immunization indicate that CD4 ϩ T cells induced by protein vaccines also produce effector cytokines.…”

Systemic Flagellin Immunization Stimulates Mucosal CD103+ Dendritic Cells and Drives Foxp3+ Regulatory T Cell and IgA Responses in the Mesenteric Lymph Node

“…Nevertheless, systemically administered FljB, another Salmonella Typhimurium flagellin, has been administered to humans without notable inflammation-associated symptoms such as fever (56), although it is unclear what impact this has on IgA or mucosal responses. Furthermore, we and others have shown that soluble flagellin can induce Th2 responses, and these may help counter some of the inflammatory effects induced by flagellin on the innate immune system (21,22,28,57). Further evidence that flagellin may not produce overt local inflammation in the intestine is that during inflammatory conditions, CD103 + DCs are impaired at driving tolerogenic responses (58).…”

T Regulatory and Primed Uncommitted CD4 T Cells Express CD73, Which Suppresses Effector CD4 T Cells by Converting 5′-Adenosine Monophosphate to Adenosine

“…Thpp cells may be appropriate for temporarily suppressing acute antipathogen responses that are causing excessive pathology and, in addition, the Thpp cells would retain the potential to differentiate later into strong effector (e.g., Th1 or Th2) phenotypes (24,59). In contrast, Treg cells would be more suitable for long-term suppression of autoimmune anti-inflammatory responses, without the risk of future differentiation into effector cells.…”