✨#ImmuneDictionary✨is out today in @Nature!
Paper nature.com
Software immune-dictionary.org
We created scRNA-seq dictionary of 17+ immune cell types responding to 86 cytokines in vivo, discovered the immune system is far more complex than previously known 1/
Paper nature.com
Software immune-dictionary.org
We created scRNA-seq dictionary of 17+ immune cell types responding to 86 cytokines in vivo, discovered the immune system is far more complex than previously known 1/
immune-dictionary.org
Immune Dictionary App - Default
Launching Immune Dictionary App... This app has been stopped, you can now close this tab. Restart ap...
nature.com/articles/s4158…
Dictionary of immune responses to cytokines at single-cell resolution
Nature - An extensive global transcriptomics analysis of in vivo responses to 86 cytokines across mo...
Every field needs a reference as a foundation for understanding the subject.
Chemistry has Periodic Table of Elements. Genomics has the Human Genome RefSeq...
But such a reference is missing in the field of #Immunology.
#ImmuneDictionary 2/
Chemistry has Periodic Table of Elements. Genomics has the Human Genome RefSeq...
But such a reference is missing in the field of #Immunology.
#ImmuneDictionary 2/
The immune system is coordinated by #cytokines - tiny molecules that instruct immune cells what to do.
There are over a million studies on cytokines, and billions $ drugs target/use cytokines to treat #arthritis, #COVID19, #allergies, #cancer, #hepatitis, #heartdisease, etc. 3/
There are over a million studies on cytokines, and billions $ drugs target/use cytokines to treat #arthritis, #COVID19, #allergies, #cancer, #hepatitis, #heartdisease, etc. 3/
Despite the central role of #cytokines in immune function, we never had a global view of how every immune cell type responds to every cytokine.
The large number of cytokines and immune cell types and complex cellular responses make it seem intractable.
#ImmuneDictionary 4/
The large number of cytokines and immune cell types and complex cellular responses make it seem intractable.
#ImmuneDictionary 4/
In @Nature we systematically measured how every major #gene (>10,000) in every major #immune cell type (>17) responds to every major #cytokine (=86) in vivo,
forming the basis of the #ImmuneDictionary and its companion software #ImmuneResponseEnrichmentAnalysis (#IREA).
5/
forming the basis of the #ImmuneDictionary and its companion software #ImmuneResponseEnrichmentAnalysis (#IREA).
5/
We profiled #scRNAseq of 386,703 cells and uncovered 17+ immune cell types in lymph nodes.
Well-known cytokine-responsive genes, such as Il4i1 in response to IL-4, Tnfaip3 in response to TNF, are robustly upregulated in our dictionary.
#ImmuneDictionary 6/
Well-known cytokine-responsive genes, such as Il4i1 in response to IL-4, Tnfaip3 in response to TNF, are robustly upregulated in our dictionary.
#ImmuneDictionary 6/
We mapped how every major #immune cell type responds to every major #cytokine in vivo.
IL-1, IL-2/IL-13/TSLP, β-chain, IL-6/IL-12, IL-10, IL-17, interferon, TNF, complement, growth factor, TGF-β...
Many of these responses have never been characterized.
#ImmuneDictionary 7/
IL-1, IL-2/IL-13/TSLP, β-chain, IL-6/IL-12, IL-10, IL-17, interferon, TNF, complement, growth factor, TGF-β...
Many of these responses have never been characterized.
#ImmuneDictionary 7/
Data quality is extremely high. We ensured that cytokines were used fresh, all samples were processed consistently, batch effect was minimal, every cell type could access the injected cytokine, and responses were highly reproducible across biological replicates.
8/
8/
We found that cytokines induce highly cell-type-specific effects. In response to IL-1β or TNF for instance, different cell types upregulated different sets of genes.
#ImmuneDictionary 9/
#ImmuneDictionary 9/
#ImmuneDictionary allows us to perform a global analysis across the entire transcriptome across all cell types. Using gene program analysis, we found that every cell type uses a different gene program in response to IL-1β, leading to a coordinated multi-cellular response. 10/
Some cell-type-specific responses could be secondary cytokine cascade effects in vivo.
IL-2/12/15/18 induced IFNγ upregulation in NK cells and IFNγ signatures in other cells, revealing secondary in vivo effects to cytokine therapies not often considered
#ImmuneDictionary 11/
IL-2/12/15/18 induced IFNγ upregulation in NK cells and IFNγ signatures in other cells, revealing secondary in vivo effects to cytokine therapies not often considered
#ImmuneDictionary 11/
Cytokines induce macrophage polarization into M1-like state by IFNγ, or M2-like by IL-4.
We found not only macrophages - every immune cell type is polarized into diverse states by cytokines, and mapped 66 polarization states across immune cell types.
#ImmuneDictionary 12/
We found not only macrophages - every immune cell type is polarized into diverse states by cytokines, and mapped 66 polarization states across immune cell types.
#ImmuneDictionary 12/
We identified well-established cytokine-driven cell polarization states.
IFNγ drives macrophages into a "Mac-b" state, and IL-4/IL-13 drive macrophages into a "Mac-e" state.
"Mac-a", "Mac-c", and "Mac-d" were driven by other cytokines.
#ImmuneDictionary 13/
IFNγ drives macrophages into a "Mac-b" state, and IL-4/IL-13 drive macrophages into a "Mac-e" state.
"Mac-a", "Mac-c", and "Mac-d" were driven by other cytokines.
#ImmuneDictionary 13/
We identified 4 NK cell polarization states.
Known ones:
"NK-a" is induced by type I interferons to express ISGs
"NK-e" is induced by IL-2, IL-12, or IL-15 to express cytotoxic molecules
Unknown ones:
"NK-c" is induced by IL-1
"NK-f" is induced by IL-18
#ImmuneDictionary 14/
Known ones:
"NK-a" is induced by type I interferons to express ISGs
"NK-e" is induced by IL-2, IL-12, or IL-15 to express cytotoxic molecules
Unknown ones:
"NK-c" is induced by IL-1
"NK-f" is induced by IL-18
#ImmuneDictionary 14/
New NK cell polarization states:
"NK-c", induced by IL-1, overexpresses IFNγ receptor.
"NK-f", induced by IL-18, overexpresses >1000 genes, including proto-ongogene Myc, which may enhance NK cell growth/proliferation.
#ImmuneDictionary 15/
"NK-c", induced by IL-1, overexpresses IFNγ receptor.
"NK-f", induced by IL-18, overexpresses >1000 genes, including proto-ongogene Myc, which may enhance NK cell growth/proliferation.
#ImmuneDictionary 15/
More views on cytokine effects on NK cells.
86 UMAPs showing the effects of each of the 86 cytokines on NK cells.
#ImmuneDictionary 16/
86 UMAPs showing the effects of each of the 86 cytokines on NK cells.
#ImmuneDictionary 16/
As a dictionary, we created a page for each immune cell type.
B cells and other lymphocytes are typically studied in the context of antigen stim.
We found in the absence of antigens, cytokines alone can induce lymphocytes into diverse states.
#ImmuneDictionary 17/
B cells and other lymphocytes are typically studied in the context of antigen stim.
We found in the absence of antigens, cytokines alone can induce lymphocytes into diverse states.
#ImmuneDictionary 17/
We performed a global analysis of the 66 polarization states identified.
We found that some states are shared across immune cell types.
Every immune cell type has an ISG I state induced by type I interferon. Many also have an ISG II state by IFNγ.
#ImmuneDictionary 18/
We found that some states are shared across immune cell types.
Every immune cell type has an ISG I state induced by type I interferon. Many also have an ISG II state by IFNγ.
#ImmuneDictionary 18/
We also found unique states for some cell types.
Such as IL-10 induced "cDC1-f" state, IL-1α/β induced "NK-c" state, and IL-36α induced "pDC-e" state.
#ImmuneDictionary 19/
Such as IL-10 induced "cDC1-f" state, IL-1α/β induced "NK-c" state, and IL-36α induced "pDC-e" state.
#ImmuneDictionary 19/
We mapped cytokine and cytokine receptor gene expression by cell type.
One can look up which immune cell type produces which cytokine, under stimulation or not.
#ImmuneDictionary 20/
One can look up which immune cell type produces which cytokine, under stimulation or not.
#ImmuneDictionary 20/
Stromal cells, and rare immune cell types, such as basophils and ILCs, produce a large number of cytokines.
Basophils are extremely rare in lymph nodes, yet they express many cytokines, including important cytokines IL-4 and IL-6.
#ImmuneDictionary 21/
Basophils are extremely rare in lymph nodes, yet they express many cytokines, including important cytokines IL-4 and IL-6.
#ImmuneDictionary 21/
Based on cytokine production and cytokine response, we created cell-cell interactome charting available channels for cell communication via cytokines.
A high level of interconnectivity in the immune system is revealed from a dense cell-cell interactome.
#ImmuneDictionary 22/
A high level of interconnectivity in the immune system is revealed from a dense cell-cell interactome.
#ImmuneDictionary 22/
Finally, we introduce #ImmuneResponseEnrichmentAnalysis, or #IREA, the companion software for #ImmuneDictionary that allows any researcher to better analyze their data.
It is similar to GO pathway enrichment analysis, but much more refined for studying immune processes. 23/
It is similar to GO pathway enrichment analysis, but much more refined for studying immune processes. 23/
#ImmuneResponseEnrichmentAnalysis compares user data with the #ImmuneDictionary reference data.
It then shows
1) Immune cell polarization
2) Cytokine responses
3) Cytokine network
#IREA has revealed key cytokines in cancer, COVID, hepatitis, and lupus, in humans and mice. 24/
It then shows
1) Immune cell polarization
2) Cytokine responses
3) Cytokine network
#IREA has revealed key cytokines in cancer, COVID, hepatitis, and lupus, in humans and mice. 24/
I thank my coauthors, mentors, mentees, cytokine experts for working together on this enormous #ImmuneDictionary project.
Teddy, Shuqiang, Aileen, Jorge, Chris, Derin, Cathy, Ernest, Lawrence, Brianna. Especially my former mentor #NirHacohen
@broadinstitute @mit_hst @Harvard
Teddy, Shuqiang, Aileen, Jorge, Chris, Derin, Cathy, Ernest, Lawrence, Brianna. Especially my former mentor #NirHacohen
@broadinstitute @mit_hst @Harvard
Our Immune Dictionary portal is currently having unprecedented traffic. We are looking into bringing it back up. Thank you for your patience.
"Dictionary" image credit -- SayoStudio & Ang Cui
جاري تحميل الاقتراحات...