Immune Netw.  2017 Dec;17(6):365-377. 10.4110/in.2017.17.6.365.

Lineage Differentiation Program of Invariant Natural Killer T Cells

• Kwon DI
• Lee YJ

• KMID: 2400623
• DOI: http://doi.org/10.4110/in.2017.17.6.365

Abstract

Invariant natural killer T (iNKT) cells are innate T cells restricted by CD1d molecules. They are positively selected in the thymic cortex and migrate to the medullary area, in which they differentiate into 3 different lineages. Promyelocytic leukemia zinc finger (PLZF) modulates this process, and PLZFhigh, PLZFintermediate, and PLZFlow iNKT cells are designated as NKT2, NKT17, and NKT1 cells, respectively. Analogous to conventional helper CD4 T cells, each subset expresses distinct combinations of transcription factors and produces different cytokines. In lymphoid organs, iNKT subsets have unique localizations, which determine their cytokine responses upon antigenic challenge. The lineage differentiation programs of iNKT cells are differentially regulated in various mice strains in a cell-intrinsic manner, and BALB/c mice contain a high frequency of NKT2 cells. In the thymic medulla, steady state IL-4 from NKT2 cells directly conditions CD8 T cells to become memory-like cells expressing Eomesodermin, which function as premade memory effectors. The genetic signature of iNKT cells is more similar to that of γδ T cells and innate lymphoid cells (ILCs) than of conventional helper T cells, suggesting that ILCs and innate T cells share common developmental programs.

Keyword

Natural killer T cells; Thymus gland; Growth and development

MeSH Terms

Animals
Cytokines
Growth and Development
Interleukin-4
Leukemia
Lymphocytes
Memory
Mice
Natural Killer T-Cells*
T-Lymphocytes
T-Lymphocytes, Helper-Inducer
Thymus Gland
Transcription Factors
Zinc Fingers
Cytokines
Interleukin-4
Transcription Factors

Figure

• 

  Figure 1 CD8 SP thymocytes become memory-like CD8+ T cells by IL-4 produced from PLZFhigh T cells. ETPs from bone marrow migrate to the thymus and differentiate into CD8 or CD4 SP thymocytes in the medulla. In WT BALB/c mice, IL-4 from iNKT cells conditions SP thymocytes to become memory-like cells expressing Eomes. CD4 SP thymocytes (dotted line) are much less efficient to become Eomes-positive memory-like cells compared to CD8 SP thymocytes (solid line). These features are also seen in genetically altered B6 mice (listed on the right side), in which PLZF-positive iNKT or γδ T cells expand. SP, single positive; ETP, early T cell progenitor; DP, double positive.

• 

  Figure 2 Comparison between the linear maturation and lineage differentiation models of iNKT cell development. Invariant TCR-expressing thymocytes are positively selected by CD1d+ cortical thymocytes. In the linear maturation model, NKT cells that produce IL-4 or IL-17 are considered immature, while mature cells produce IFN-γ. In the lineage differentiation model, undifferentiated PLZFhigh NKTp give rise to terminally differentiated NKT1, NKT2, and NKT17 cells.

• 

  Figure 3 Schematic representation of iNKT cell development and localization in the thymus. Upon positive selection, NKTp cells move to the medullary area and undergo differentiation into various subsets. NKT2 cells produce IL-4 at steady state, which can condition medullary thymocytes to phosphorylate STAT6 and express Eomes. A portion of NKT1 and NKT17 cells migrate back to the cortical area. STAT6, signal transducer and activator of transcription 6.

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