Th17 cells—a new T cell lineage

CD4+ T helper cells are critical mediators of the cellular immune response. For many years, due to cytokine expression patterns, it was thought that CD4+ T helper cells existed as a dichotomy of lineages named Th1 and Th2. However, as these subsets were analyzed more closely, it became apparent that the T helper cell population was not limited to these two subsets. Although it has long been appreciated that IL-17 (also known as IL-17A) production by T cells is required for protection against some pathogens, in 2000 it was demonstrated that IL-17A was produced by a unique subset of T helper cells. Subsequently, it was definitively shown that T cells could differentiate into IL-17-producing cells in vitro and in vivo independently of Th1 or Th2 cell development thereby establishing Th17 cells as a unique T helper cell lineage. Functionally, Th17 cells play a role in host defense against extracellular pathogens by mediating the recruitment of neutrophils and macrophages to infected tissues. Moreover, it has become evident that aberrant regulation of Th17 cells may play a significant role in the pathogenesis of multiple inflammatory and autoimmune disorders.

Differentiation of Th17 cells is controlled by a “master-regulator” transcription factor, ROR gamma t, which directs a specific and heritable gene expression profile. ROR gamma t was initially identified as a thymus-specific isoform of ROR gamma, and later, it was discovered that ROR gamma t is also expressed in Th17 cells. ROR gamma t deficiency results in diminished Th17 activity and severely reduced expression of IL-17.


Th17 cell lineage diagram


Properties of T cell helper lineages

Feature Th1 Th2 Th9 Th17 Th22 Treg Tfh
Surface Expression

IL-12RB2

IFN gamma R

Tim3

IL-17RB

Tim1

 --

IL-1R1

IL-12RB

IL-23R

CCR6

CD161

IL-13Ra1

PDGFR

CCR10

CD25

CD39

CD73

CD101

CD127lo

FR4

GITR / AITR

CD84

CXCR5

IL-6R

IL-21R

gp130

Unique Cytokine Expression IFN gamma

IL-4

IL-5

IL-13

IL-9

IL-17A

IL-17F

IL-17AF

IL-21

IL-22

IL-22

TNF alpha

TGF beta

 

IL-6

Master Regulator Transcription Factor T-bet Gata-3 -- ROR gamma t -- Foxp3 BCL6
STAT Regulators

STAT1

STAT4

STAT6 -- STAT3 -- STAT5 STAT3
Polarizing Cytokines

IL-12

IFN gamma

IL-27

IL-4

IL-25

IL-4

TGF beta

IL-6

TGF beta

IL-21

TNF alpha

IL-6

TGF beta

IL-6

IL-21

CXCL13

Th17 cell function

Th17 cells are not only distinct from other Th cells in their gene expression and regulation, but also in terms of their biological function. Th17 cells, by virtue of their production of IL-17 and IL-17F, are generally thought to be pro-inflammatory and play an important role in host defense against infection, by recruiting neutrophils and macrophages to infected tissues. Although the hallmark of Th17 cells is the expression of IL-17, additional molecules have been identified by microarray analysis as being selectively expressed by Th17 cells.

Since their initial discovery it has become clear that Th17 cells also express the cytokines IL-21 and IL-22. IL-21 is not only expressed at high levels by Th17 cells, but it also binds to its receptor, composed of IL-21R and the common γ chain, expressed by Th17 cells to act in an autocrine manner. Expression of IL-21 is dependent on STAT3-mediated IL-6 signaling in Th17 cells and is thought to act in synergy with TGFβ to promote Th17 differentiation. Th17-secreted IL-22 binds to its receptor on target cells to induce the expression of anti-microbial peptides beta-defensin-2 and beta-defensin-3. Recently, it was demonstrated that IL-22 is able to protect hosts against bacterial infections of the lungs and gut.

We provide a complete solution for assessing the function of Th17 cells. All of our eBioscience™ reagents are validated in relevant Th17 model systems and in gene-deficient models if necessary, to ensure they are the most sensitive and specific reagents available. The most complete set of antibodies for detection of Th17 cytokines by flow cytometry allows study of Th17 development at the single-cell level. Our immunoassay products enable analysis of analytes in either serum or tissue culture supernatant and our FlowCytomix™ allows multi-parameter analysis of cytokines from small sample volumes.

Simultaneous analysis of complete Th17 cytokine expression

Human Th17 Cytokine Analysis. Staining of Th17-polarized, PMA-, ionomycin- and Brefeldin A–treated CD4-enriched human PBMCs with the Human Th17 Cytokine Staining Panel. Lymphocytes were gated for staining of CD4 eFluor™ 450 and IL-17A FITC (blue) and then analyzed for staining of IL-17F PE, IL-21 Alexa Fluor™ 647 and IL-22 PerCP-eFluor™ 710. Quadrant lines were set based on staining of Th17-polarized cells treated with Brefeldin A but not PMA and ionomycin.


Mouse Th17 Cytokine Analysis. Staining of Th17-polarized, PMA-, ionomycin- and Brefeldin A–treated Balb/c splenocytes with the Mouse Th17 Cytokine Staining Panel. Lymphocytes were gated on CD4 eFluor™ 450 and analyzed for staining of IL-17A FITC, IL-17F PE, IL-22 PerCP-eFluor™ 710 and IL-21 Alexa Fluor™ 647. Quadrant lines were set based on staining of Th17-polarized cells treated with Brefeldin A but not PMA and ionomycin.


References