Tag Archives: my research

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,