Innate Lymphoid Cells Flashcards
NK Cell Review
What cytokine NK cells produce?
Which germiline receptors NK cells use?
- NK cells fill a critical gap between non-lymphocyte innate and lymphocyte-mediated adaptive immunity
- NK cells produce robust IFN-gamma to activate immunity and directly kill cells.
- NK cells use germiline receptors like NKG2D
Cell Types Blur Adapative vs. Innate
ILC and unconventional provide a critical role early in life, and early in infection
Unconventional T-Cells
Includes: NKT, MAIT, gamma/delta T cells, CD8 double alpha
Develop via V(D)J and Rag
However, cells do not react with classical peptide-loaded MHC
Use conserved TCR segments to react with nonclassical MHC or other receptors
Often express NK cell receptors (e.g. NKG2D, CD94, KIRs)
Unconventional T-Cells
Unconventional T-Cells exit the thymus fully functional without prior stimulus
They typically make helper cytokines. But, may have some cytotoxic capability and granules
Unconventional T-Cells
- Unconventional T-Cells depend upon conserved T-Cell receptor segments.
- In conventional alpha-beta T-Cells, V(D)J recombination can choose between an unrestricted repertoirse of segments.
- Valpha14 has identical sequence across multiple strains of mouse thymus.
- Thus, unlike most other TCR segements, Valpha14 is conserved.
- Further 2-4% of thymocytes are Valpha14+. which is 1000x more than exprected by chance.
Unconventional T-Cells
(NKT, MAIT, and gamma-delta T-Cell)
Recognize nonclassical MHC, which are distinct than the polymorphic MHC recognized by classical T-Cells.
MR1 presents vitamins B derivates, which is recognized by Balpha19 on MAIT cells,
CD1 presents lipids, which is recognized by Valpha14 (m) on NKT-cells
NK cell receptors are non-classical MHC
Mucosal-Assocaited Invariant T-Cell
(MAIT)
- Up to 10% of human blood T-Cells
- Thymus development with strict TCR
- Human: Valpha7.2 and Valpha33
- Mouse: Valpha19, Jalpha33 paired with Vbeta2 or Vbeta13
- Sense microbial riboflavin metabolims captured by extracellular environment and displayed on MR1
Natural Killer T (NKT) Cellls
CD-1 restricted T-cells
Two groups:
* Type 1 NKT have restricted Valpha24-Jalpha18 (h) or Valpha14 (m) receptor for CD1.
* Type 2 NKT bind CD1 but have a diverse repertoire
NKT recognize microbial glycolipids, phospholipids, lipopeptide antigens.
Gamma-Delta T cells
Arise from double negative (DN) thymocytes that recombine TCRg+TCRd.
Express combinations of TCR Vgamma and Vdelta, with varying specificity.
Highly abundant in skin and barrier tissues and intra epithelial sites
Recognize:
* Phosphoantigens
* Others
Polarization is dependent upon Vgamma and Vdelta combination rearranges in the thymus.
Example: Vgamma9Vdelta2+ Tcells recognize BTN2A1 that is stabilized by phosphopeptides. In response, they make IFN-gamma.
Gamma-Delta T cells
CD8 - CD4 - CD8doublealpha
(Part 1)
Non-functional T-Cells
Reminder:
* CD8alpha binds MHC-I
* CD8a/b is complete co-receptor for signaling
CD4-CD8-CD8doublealpha arise from double negative precursors and migrate to mucosa epithelia.
Oligoclonal, but TGF-Beta induces CD8doublealpha, which downregulates TCR.
Express:
* NKG2D (recognize stress)
* TRAIL
CD8 - CD4 - CD8doublealpha
(Part 2)
- Positioned at barrier sites (skin, instestine, lung, etc.)
- Dominate intra epithelial lymphocytes (IEL)
- Most abundant in proximal small intestine, where 1 for every 10 epithelial cell.
- Embedded and migrate within and between epithelial cells.
- Able to migrate to sites of infection, cell stress, DNA damage (i.e. NKG2D ligands), rapidly supporting immunity
Intra Epithelial Lymphocytes
(IEL)
Unconventional T-Cells
Review Reference Slide
Unconventional T-cells moslty make helper cytokines, but can be cytotoxic
B2M is needed for MHC-I stabilization, which includes non-classical MHC-I such as MR1, CD1, HFE (iron homeostasis), and ZAG (fatty acid homeostasis).
Which unconventional T-Cell subset requires B2M on the target recognition?
NKT
Gamma-Delta T-cells are some others that these subsets.
TAP is needed to load peptide to MHC-I in the ER.
What T-cell responses should be TAP-dependent and TAP-dependent?
- TAP-dependent -> NKT cells
- TAP-independent -> MAIT cells
Innate Lymphoid Cells
Cell Types Blur Adapative vs. Innate
Let’s take a T-helper cell and make it innate
Innate Lymphoid Cells
Programming
- Pathogen and/or tissue resident patterns
- Signal
- Polarization-specific STAT
- Lineage determining TF
- Effector cytokine
Differentation depends on:
Innate Lymphoid Cells
Type 3 ILC
Type 3 ILC induce barrier healing and defense
Maintain “immunologic tone” of tissues barrier reinforcement ILC3s participate in containment of commensals
Innate Lymphoid Cells
Type 3 ILC
Type 3 ILC require AHR to make IL-22
Innate Lymphoid Cells
ILC2
To what signals ILC2 respond?
ILC2 respond to neuronal and adipose signales
There are a vast repertoire of receptors for neuropeptides
Innate Lymphoid Cells
ILC1
How do ILC1 acts?
ILC1 acts as tissue protectors
