5 Cytokines That Are Just Ballin’

I blame Buzzfeed. I really do. But, really, why not have a GIF-studded listicle of cytokines? Am I crazy? :)

1) IL-10

You know how inflammation can be a clusterf**k sometimes? Well, IL-10, and the other cytokines of that family are the ones that lay down the law. When inflammation needs to be quieted, IL-10 will insert its bad 18.5 kDa self into the fray, and, via a JAK1-STAT3 signaling axis will induce the anergy of IL-2 dependent Th1 cells. IL-10 is the friend who knows when your rager of a party has run its course, the friend who will save your IL-2-drunk ass from alcohol poisoning. In a nutshell, this is IL-10.

IL-10 wants you to know that the party is over.

2) IL-2

Interleukin 2 is a 133 amino acids of a roaring good time. IL-2 is the milkshake that brings almost all the important inflammtory cells to the yard. As antigenically/mitogenically stimulated T-cells crank out IL-2, it brings about its own proliferation by turning on IL-2 producing genes in T-cells and macrophages, but also causing IL-2 receptor upregulation on T-cells, B-cells, macrophages, and NK cells. Basically, IL-2 is what drives a robust adaptive response to any nasties who think they know what’s up. Really, bacteria/viruses/anything else, IL-2 always knows what’s up. Don’t even. Like, nope. “Cause IL-2 does not give a shit.

The World According to IL-2

3) TGF-β1

Transforming Growth Factor Beta is the belle of the ball, one of the reigning divas of the immune response, a major Prom Queen candidate… One of the reasons for this is that the cytokine is super-involved: it has important roles in cell fate determination, angiogenesis, morphogenesis and regulation of certain hormones, just to name a few things off of the top of my head. In the immune response, however, TFG-beta is involved in both the initiation and resolution of inflammation, like its buddy IL-10, up there. While TGF-beta has several productive interactions with T-cells, NK cells and macrophages, my favourite TGF-beta trick involves its interactions with the extra-cellular matrix wherein in brings about fibrosis. This is an important consequence for, say, wound-healing. The signaling axis involved is the sort of thing I want to party with forever.

TGF-beta1, telling it how it is.

4) TSLP

TSLP is slowly emerging as THE Queen Bitch of the Th2 immune response–sorry, IL-4. Love ya, but, yeah…

Thymic Stromal Lymphopoeitin is involved in basophil development, the proliferation of dendritic cells armed with a Th2 programme or even a tolerogenic one, the homeostasis of NKT and CD4+ T-cell populations, and also this fascinating phenomenon known as The Atopic March. This is, well, “a process”, shall we say, that causes allergic diseases to progress: from, say, atopic dermatitis to allergic asthma or allergic rhinitis or both. TSLP is purported to be the one cytokine that fine tunes the Th2 response to seemingly leap from one organ to the next. Disclaimer: I don’t strictly understand the machinations of the Atopic March; take my explanation slightly salted! :)

Dear Th2 Response, Yep. Love, TSLP.

5) IL-33

Interleukin-33 is your epithelial cells’ way of letting you know that shit is going down. IL-33, under necrotizing circumstances, will be released from the dying cells and induce a potent cytotoxic T-cell response. IL-33 is one to watch out for, really, because, structurally, it has similarities with the IL-1 Family of cytokines, but it doesn’t *need* to be cleaved by Caspase 1 to be active. It also has a nuclear localization signal which suggests more “traditional” cytokine-y roles. But what are they, really? IL-33 is seen as important in both allergic diseases, as well as good ol’ antimicrobial defence. The destiny and secrets of this cytokine (alarmin?) seem very promising, indeed!

IL-33 is coming!

Take care now,

A.


My Project, Myself

My project and I? We’re in a good place. We don’t hate each other. This isn’t like the Eminem-Rihanna thing that had begun to happen with my MS thesis. Oh, Lord. Those were dark, drunk days…

I will admit, I was a bit calculative when I picked my current lab: we work with NKT cells, a flavour of immunocyte that isn’t completely understood. Thus, there is a lot to do, lots of questions to ask, lots to answer, and lots of new questions to raise….However, real-talk: I don’t get these cells. I don’t understand them. I don’t understand where their so-called “self” antigens come from. I don’t understand how they get to, y’know, BE. This doesn’t bother me, though, because I imagine that this is part of the process of getting this here PhD. If I knew this already, why in the world would I be in the lab setting up experiments?

My work focuses on the adhesion and migration behaviour of NKT cells in response to differential integrin signaling. The project was born out of this brilliant paper by Dr. Seddon Thomas, whom I admire from afar. In truth, we don’t know what makes NKT cells wanna travel, and if they do, where do they go? Dr. Thomas’s work seems to suggest that NKT cells home to the sinusoids of the liver given the high concentration of ICAM-1 there. I’ll buy it. The paper also suggests that PLZF (zinc-finger protein, transcription factor, controller of cell cycles and fates) is the key regulator of LFA-1 abundance on the NKT cell surface. Sounds good to me…mainly because it opens up all these avenues for the impact of NKT chemokine and integrin/receptor profiles on pathogenesis of inflammatory diseases.

NKT cells are a big deal in asthma. So, what causes them to home to or away from the lung? Is PLZF responsible, again? There are other things. Things I am not at liberty to speak of, but, needless to say, am chuffed about.

So, here we are: my project and I, eyeing each other gingerly, wondering what shall happen next…

Take care now,

A.


Whore

It was with great disgust that I read the account of Dr. Danielle Lee being a called an “urban whore” for not wanting to write for an obscure science blog since they didn’t offer financial compensation to their bloggers.

Misogyny AND racism! Well done, Biology-Online! You stay classy!

What makes this situation even worse is that Scientific American, where Dr. Lee blogs, forfeited a wonderful opportunity to create a teachable moment out of this, one that highlighted the discrimination that women in science face, and further scientists of colour face.  They deleted Dr. Lee’s post, in what seems to be a move to protect themselves from negative publicity, and, perhaps loss of revenue.

Think of how dehumanizing Biology-Online’s editor’s words are: “urban whore” robs Dr. Lee of the science that she does. It robs her of her mind, and unflinchingly places the focus on her body, as if to say that her intellectual contributions are equivalent to what a prostitute working a corner does.

Why the hate, I ask? Just because she asked for compensation? We live in a world where advances in the biological sciences are happening at breakneck speed, and where there is a need for stellar scientists, there is also a need for stellar scientist-communicators who can share the wonder and awe of research with the common populace. Dr. Lee is one such writer. Her posts are that rare tonic of witty and edifying. Shame! Shame on Biology-Online for reducing one so brilliant to a slab of meat that gets traded on an ugly marketplace, and shame on Scientific American for not standing by one of their finest.

Take care now,

A.


Narcissus, A Natural Killer, and His Self-love

If you are an old-school immunologist, you will probably accuse me of sacrilege if I revealed the focus of my graduate work to you. You see, I work on and with an innate T-cell population called the Natural Killer T-cells, or NKT cells. Yes, you read that right. Innate T-cell. Deal with it!

NKT cells were discovered 20-ish years ago and so you know that they aren’t a fad. They are a distinct population of T-cells that have the NK1.1 (CD161) marker (associated with NK cells), and, while some may express a semi-invariant version of the TCR one associates with conventional αβ T-cells using the Vα24-Jα18 and Vβ11 TCR genes, for example, others (Type II NKT cells) have more variety in the kinds of T-cell receptors they express. Both Type I and Type II NKT cells distinguish themselves from conventional T-cells by being CD1d restricted (as opposed to the MHC restriction we’ve come to know and love, but only as delimited by its strict 8-11-amino-acid-linear-peptide criteria!). However, the two types of NKT cells distinguish themselves from each other via a weird-ass, sponge-born lipid called α-galactosylceramide, or alpha-galcer. Type II NKT cells don’t respond to alpha-galcer, while Type I’s do.

What I like about NKT cells is that they represent the best kind of immunocyte: the kind that bridges the gaps of communication between seemingly “pureblood” populations of innate and adaptive cells. That NKT cells can be autoreactive but also respond to foreign, potentially pathogenic antigens, that NKT cells can secrete signature Th1, Th2 and Th17 cytokines are all signs that this is a cell type that can swing both ways, or as many ways as there may be.

The element of narcissism that NKT cells seem to come with is also a major turn on for this young experimental scientist, You see, NKT cells can respond to self-antigens as well. The means of doing this are, quite frankly, awe-inspiring. It makes sense that the CD1d receptor has evolved to enable the α-linked microbial glycolipids to fit perfectly perpendicularly in its groove for effiicient antigen presentation to the NKT TCR. That the NKT TCR manages to flatten the β-linked mammalian antigens to fit it is nothing short of, well, unexpected, Mainly, because you’d expect the TCR to be the one to make the structural compromise, as it were. Is this something that NKT cells learn as they terminally differentiate? Is this the test that they have to pass in order to be selected for? The jury is still out…

Clearly, the implications of self-antigen reactivity are amazing in terms of the roles that NKT cells may play in graft rejection, anti-tumor immunity and immunomodulation. It also these very roles that define what exactly NKT cells do in the larger picture that is The Immune Response. Tracing the thymic development of NKT cells tells us that three distinct lineages of NKT cells exist (so far, anyway!): you have your T-bet hi, PLZF low, IFNγ and IL-4-producing, IL2R-expressing, CD4 +ve or -ve, NKR+, NKT1 cells; the transcription factor that dominates the NKT2 type cells is GATA3 and these cells are CD4+ and crank out IL-4 and IL-13, while bearing the IL17 receptor Rb. And, finally, the NKT17 type that are both CD4 and NKR negative and sweat IL-22 and IL17 and express receptors for IL-17 and IL-23. Sound familiar?

Just think! In a system of cells so geared towards specificity and an efficient division of the labour that is the immune response, there exists a population dedicated to fluidity in terms of the things they respond to and the phenotypes they subscribe to. NKT cells, to me, represent exactly what makes immunology work for me. If biochemistry and such as the Romance Languages, immunology is like English in that there are more exceptions to rules than there are adherents. It is a field that enables you to dream big, because everything is possible, though, at first, nothing makes sense!

Take care now,

A.

 


We Don’t SMAC and Tell in This Business…

The number of T-helper subsets is staggering.  Well, staggering compared to the initial See-Saw* relationship we envisioned existing between the Th1 and Th2 profiles. A lot is known about these subsets, their hallmark cytokines, the transcription factors they couple with, and what musical genres really get them in a mood for proliferation…not really.

What is not known, however, shockingly, is what exactly initiates signaling at the T-cell Receptor (TCR)?  Weird, isn’t it? We got so caught up with all the drama in the middle of the story that we never bothered to ask how the story began?

The TCR is as elegantly put together and enigmatic as Don Draper. It is a membrane-spanning heterodimer made up of an elaborate, two-layered bow-tie  of β-pleated sheets: the classical immunoglobulin fold, as it were. The variable regions of this heterodimer, the Vα and the Vβ, interact via their bottom β-sheets. The constant regions also conform to the immunoglobulin fold but with one distinction: the top-most β-sheet of the Cα region is replaced by two linker-like strands. The significance of this pocket is not known. Yet.  The extra-cellular domain of the TCR has the aspect of the antigen-binding fragment (or Fab) region of an antibody molecule. That the extracellular domain of the TCR is what sidles up to the edges of a peptide-loaded MHC (pMHC) molecule to sample said peptide, this structural feature, so adept at recognition, makes a world of sense.

A co-conspirator of the TCR is CD3. Or rather, the four polypeptide chains(ε, γ, δ and ε)  that make up CD3.  Sort of the Roger Sterling to the TCR’s Don Draper, the intra-cellular regions of CD3 bear  Immunoreceptor Tyrosine-based Activation Motifs (ITAMs), the phosphorylation of which is one of early moments of signal transduction that activates a T-cell. In a lovingly rendered and thoroughly detailed treatment of how the TCR and CD3 fit together, Dr. Mike Kuhns of the University of Arizona (whom I’ve had the pleasure of dining with!) describes how the CD3δε and the CD3γε, in an “open face orientation”, dock on either side of the TCR. This not only provides evidence for there being sidedness for the TCR-CD3 complex, but also that the clustering of the complexes isn’t a random pile-up of multimeric complexes that orgiastically make signalling happen.

Ah, yes, the clustering! So much contention with the clustering. Are the TCR-CD3 clusters pre-assembled or do they huddle together once the TCR is activated? But as Xie et al tell us, in the T-cell’s self-communion, LAT (Linker of Activated T-cells) and TCR microclusters just lurk beneath the cell surface membrane, ready to co-mingle with CD3 when the time is right, and migrate to what becomes the inner circle of the cluster of receptors on the cell-surface: the central supramolecular activation cluster (cSMAC). The TCRs of the cSMAC are, themselves, bedizen with a cluster of accessory molecules like LFA-1 which form the peripheral SMAC or the pSMAC. In a conversation between antigen presenting cells and T-cells: these interactions ask the rather pivotal question of, “Shall we dance?” If the answer is “We shall!”, we might see some cytokine action!

Take care now,

A.

 


Worm Me!

I cut my teeth on allergy and asthma. For my M.S., I worked in a lab that looked at hypersensitivity to Aspergillus fumigatus, a pretty common mold whose star has risen as a potential invasive/infectious disease biggie in our largely immunosuppressed world. My work concentrated on the allergenic prowess of A.fumigatus, however, and I looked more at systemic pathology rather than any particular cell-type or mediator. Of course, pathology in allergic disease is under the control of many cell types and their assorted secreted nasties, and those, in turn, are directed by cytokines secreted by CD4+ T-cells.

Now, an allergy is a propensity to an inappropriate, aberrant immune response to something that doesn’t quite warrant it. Peanuts, dander and pollen are meant to be enjoyed, brushed away…and, gee, I don’t know what one does with pollen…In allergic individuals, however, these seemingly innocuous antigens elicit a strong, inflammatory immune response, characterised by high titers of IgE, eosinophilia and the presence of hallmark Th2 cytokines like IL-4, IL-5, IL-13, IL-33, SCF and TSLP. Given that Th2 refers to a type of T-helper (type 2, specifically) response, one has to wonder why the usually on-point, meticulous T-cell has such an overreaction to Elizabeth Barrett Browning’s (which is what I would name my cat) dander.

The Hygiene Hypothesis offers an explanation. My understanding of this is that a clean, sanitary lifestyle somehow predisposes the immune system to act out against a non-immunostimulatory antigen. Now immune systems that develop in unsanitary strife of a variety of irritants and potential pathogens learn quickly to deal, and respond only to potentially problematic antigens.

Fair enough.

However, the Extended Hygiene Hypothesis takes a larger picture view of the same idea wherein it claims that the composition of gut microbes in children as well childhood infections to worms, for example, eventually influence the inflammatory response. This becomes important because it is the prevalence of chronic inflammation that unites the ostensibly different disorders of allergic asthma, atopic dermatitis, type 2 diabetes and, wait for it, depression. The Extended Hygiene Hypothesis states that early exposure to a more diverse microbial population will bring forth a worldlier immune system that shall not freak out any time the status quo is changed, thus, less allergies, and inflammation that does not overstay its welcome.

A vote in support of the above is seen in da Costa et al’s study “Schistosoma mansoni-Mediated Suppression of Allergic Airway Inflammation Requires Patency and Foxp3+ Treg Cells” published in PLoS Neglected Tropical Diseases on August 15th, 2013. The study is strong proof for the Bystander Suppression phenomenon wherein the immune response to worm antigens suppresses the similar immune response made to OVA allergen. This, to me, is a powerful observation since it gives us a glimpse into the “priorities” of the immune system, as it were. The immune system goes back to basics when faced with both an allergen and a pathogen: after all, the Th2 response evolved to deal with metazoan parasites.

Further, the authors also uncover a new putative mechanism by which suppression of airway inflammation is mediated: via T-reg cells. Foxp3+ve, CD4+ve T-cells, or regulatory T-cells are the effective voice of reason during inflammation, the voice that goes, “Shut it down!” to cells that are cranking out inflammatory factors with wild abandon. Obvious as this may seem now, as da Costa et al say, the silencing of airway inflammation has, classically, been the prerogative of regulatory B-cells and that eternal pacifist, IL-10.

So, is the worm the answer? Is it the intermediary that needs to be reintroduced into the equation so that different T-cell populations can talk and abrogate allergic inflammation? Apparently, this is a thing. It’s not as unorthodox if it sounds if research manages to unearth immunostimulatory components from worms that act as the Rosetta Stone of cytokinic communication between cell types and, ultimately, reduce allergy altogether. Could we be headed towards an age where any child who yearns for a pet is reminded that s/he bears a symbiont worm within?

Stranger things have happened. :)

Take care now,

A.


T-Cell Biology and The Young Experimental Scientist

So, I might be a little rusty. I haven’t blogged for myself in a while. My last blog was a sensationalized and very public diary of the rather sordid goings-on of my undergrad days in a very snowy, very Midwestern city– but none of that is of any consequence. Those who peopled those stories have now found spin-offs and supporting roles elsewhere. This blog is not about them. This blog is not even about me. Well, it is, but this blog is about me and the adaptive immune system, me and graduate school, and T-cells. There will always be T-cells.

Now, immunology and I: we go way back. Think 9th grade. Or was it the eighth? Who knows anymore? But, I remember making a series of holes in the worn cloth of my pencil-case imagining that the “ancient proteins that punched holes in bacteria” operated on a similar principle. There were also cells: T-cells killed, B-cells made antibodies, macrophages pigged out like jocks during football season while neutrophils, like extras from “The Devil Wears Prada” sleekly extravasated where damage control was needed. For me, that might have been the first time I wondered how? That a lot of that wasn’t quite known at the time was also exhilarating. But, I had med-school dreams: the mysteries of the immune system, esoteric as they were, were someone else’s problem.

It was during my undergrad, however, that immunology and I met again. Both of us were  older: immunology, suffuse with brand-new cytokines and transcription factors, and I awash in discovering how wonderful it was to have an open mind. Under the tutelage of a Bright Young Thing of the immunology firmament, I began to rediscover the hows that were not known when I was a ninth grader. Sound as those unknowns were, they led to newer questions. There were worlds to discover within!

What attracted me to T-cell biology more than anything else was the sense of precision, control and extroversion (if you will!) that T-cells inherently posses. In my mind, CD4+ T-cells would receive antigens (only peptides, linearised, of a precise amino-acid length and loaded onto the right kind of MHC molecule, thanks) like aristocrats languidly snatching up a letter from a tray. If the contents of the letter were of importance, these cells would snap to action: proliferate and home to the site where they were needed to direct traffic, all the while secreting cytokines with abandon, like mass texts announcing a rager of a party, recruiting more of their own and sending messages of intent or disfavour to other cells. All of them, united towards a common goal of eliminating a threat or, in more misguided cases, the self. The immune response, in the best and the worst cases, is a grandiose production, a symphony of activated cells whose cytosols, like metropolitan roads at rush hour, are inundated with proteins passing phosphoryl groups from one to the other, all the way down to the nucleus…and there are so many of these cells, their orchestrations under masterful control by CD4+ T-cells.  I am breathless thinking about it.

And so, this is the idea behind the blog: to articulate the awe I feel about adaptive cells and the cells that are intermediaries in the “Upstairs/Downstairs” situation that exists between the innate and the adaptive arms of the immune system.  As I talk to you, constant reader, I myself understand more, and everybody wins!

Take care now,

A.


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