Targeting Lymph Node Niches Enhances Type 1 Immune Responses to Immunization

Abstract

SUMMARY Generating robust CD4 + T-helper cell type 1 (Th1) responses is essential for protective vaccine-induced type 1 immunity. Here, we examine whether immunization formulation associated with enhanced vaccine efficacy promotes antigen targeting and cell recruitment into lymph node (LN) niches associated with optimal type 1 responses. Immunization with antigen and Toll-like receptor agonist emulsified in oil leads to an increased differentiation of IFNγ/TNF-α + polyfunctional Th1 cells compared to an identical immunization in saline. Oil immunization results in a rapid delivery and persistence of antigen in interfollicular regions (IFRs) of the LN, whereas without oil, antigen is distributed in the medullary region. Following oil immunization, CXCL10-producing inflammatory monocytes accumulate in the IFR, which mobilizes antigen-specific CD4 + T cells into this niche. In this microenvironment, CD4 + T cells are advantageously positioned to encounter arriving IL-12-producing inflammatory dendritic cells (DCs). These data suggest that formulations delivering antigen to the LN IFR create an inflammatory niche that can improve vaccine efficacy.

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“…A study of incomplete Freund’s adjuvant (IFA) containing mineral oil and surfactant similarly favored the use of adjuvanted vaccine and indicated that an oil formulation may further enhance efficacy ( Lian et al, 2020 ). The oil emulsion in IFA-containing immunizations better distributed both ovalbumin (antigen) and lipopolysaccharide (adjuvant), causing stronger Th1 differentiation in response to vaccination.…”

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“…The specific transcriptional program of T H1 or T SLEC effectors, T FH, and T SCM cells moves cells into spatially distinct regions of draining lymph nodes viral infection or by using specific vaccination strategies that target antigen to this region. 1,136,137 Using a dual CXCR3 ligand reporter mouse, we demonstrated that CXCR3+ CD4+ T cell movement is directed by the expression of CXCL9 and CXCL10 in this region. 7 While this study did not reveal the precise dendritic cell or stromal cell population that move T cells into this area, we have now demonstrated that type 2 conventional dendritic cells (cDC2) express high levels CXCL10 in the IFR.…”

“…This has recently been investigated for the promotion of T H1 cell differentiation in vivo. 137 This study compared soluble Toll-like receptor and antigen delivered in the mineral oil emulsion, incomplete Freund's adjuvant (IFA). The use of the oil emulsion formulation altered the antigen deposition, moving it to the IFRs, rather than the medulla of draining lymph nodes.…”

“…The IFR provides a unique lymph node niche that has a rich stromal cell network 135 . Here, antigen can be deposited, either during particulate viral infection or by using specific vaccination strategies that target antigen to this region 1,136,137 . Using a dual CXCR3 ligand reporter mouse, we demonstrated that CXCR3+ CD4+ T cell movement is directed by the expression of CXCL9 and CXCL10 in this region 7 .…”

“…133,145,146 Further, moDC promotion of T H1 differentiation is associated with their location in IFRs following vaccination. 137 Recently, Bosteel et al provided an important advance to the dendritic cell literature, revealing that these cells are not capable of antigen processing; however, they can express high levels of IL-12 to polarize effector T cells. [147][148][149] In addition to moDCs, an inflammatory subpopulation of cDC2 cells, named infDCs, has recently been characterized.…”