‘What have we learned about T cell biology from Jurkat cells?‘. A more accurate reformulation would be ‘What have we learned from Jurkat cells that’s applicable to T cell biology and what’s not?”. Unfortunately, the answer isn’t that easy to untangle from archival data.
Much like the tumor cell linebefore it, from the 1980s through the 1990s, became a heavyweight tool to understand human (TCR) biochemistry ( ). Later, Jurkat also became a popular tool to model human T cell infection by HIV. However, very much a , Jurkat‘s perceived benefits remained disproportionately the focus during this time while its harms have been considered only much more recently. Meantime, 21st century technological advances have pretty much eliminated reliance on such inherently problematic transformed (tumor) cell lines.
This answer outlines
- A brief history of the Jurkat T cell line, highlighting how the imperatives of prevailing technical limitations drove its past popularity.
- how Jurkat‘s inherent limitations in decoding TCR signaling are predicated on the fact that it is a tumor cell, has mutations and is potentially contaminated, features that cast doubt on the validity of some historical results using it.
Brief History of the Jurkat T cell line
In 1977, a cell line was derived from T cells isolated from a 14 year old boy with(ALL) (2). This cell line was eventually called Jurkat.
Back then, T cells remained very much a mystery, there was little or no consensus on how to maintain them in culture for long periods of time, a basic requirement necessary to dissect their essential properties, especially their biochemistry.
The experimental mouse model, today the backbone of immunology research, was still in its infancy as was molecular biology. Today’s technological mainstays such as gene targeting to create T cell transgenic mice and T cell transgenics with attached reporter genes to facilitate their monitoring were advances decades in the future.
Thus in this vacuum, an immortalized cell line such as Jurkat capable of being maintained in culture in perpetuity became an extremely valuable tool that in hindsight arose at the moment when most needed.
In its early years of use, Jurkat was thus used to delineate a great deal of the signal transduction pathway and molecules triggered by(TCR) signaling ( ).
Hindsight also suggests a readily available human T cell line made such research far simpler and much cheaper. No need to draft complicated study protocols, get them reviewed and approved by(IRB) in order to gain permission to bleed people to isolate their T cells in order to study them. Jurkat was thus a convenient tool to study aspects of human TCR biochemistry.
Limitations of Jurkat T cell line
Immortalized cell line versus primary, normal cell. During its early years of use, methods to culture human primary T cells didn’t exist. Even today, primary T cells simply can’t be maintained indefinitely in culture. Their long-term study requires stimulation, expansion, cloning and then immortalization (hybridization [mechanical fusing] with a partner tumor cell).
Yet, being a tumor cell, do results from Jurkat apply to normal human T cells in general? That’s simply unknowable since it’s impossible to know exactly what T cell stage Jurkat represents considering it got established and began to be used back when little was known about T cell development, activation, effector differentiation and memory formation. While papers routinely refer to Jurkat as a, at best that’s just a tenuous guess.
Mutations in many key molecules involved in the TCR signaling pathway. Tumor cells replicate uncontrollably, having broken free of biological control. Mutations in cell cycle checkpoints make such liberation possible. During its first two decades of use, how Jurkat‘s mutations might affect its TCR functioning wasn’t a focus. After all, there is an inherent tautology to unraveling signaling defects in cell lines being used to identify signaling pathways in the first place. Signaling pathways need to be comprehensively deciphered first to determine if a particular cell line has a signaling defect or two or however many the case may be.
As T cell biochemistry advanced apace by the late 1990s, some TCR signaling pathways identified using mouse T cells, T cell lines or other human T cell lines didn’t concord with those found in Jurkat. Turns out mutations in Jurkat accounted for such discrepancies.
- Today, signaling of the (PI3K) family is known to be a central feature downstream of TCR signaling. Yet, in the late 1990s-early 2000s, two key molecules that mediate PI3K signaling were found to be missing in Jurkat cells ( ). Such a fundamental signaling defect raised questions about the validity of using Jurkat as a tool to understand (human) TCR signaling ( , ).
- A 2017 analysis uploaded to the preprint server, bioRxiv, comprehensively collates the various defective pathways and key signaling molecules missing in Jurkat (
- In addition to PI3K, it points out Jurkat doesn’t express other molecules such as SHIP1 ( ), and , all now known to be important components of the TCR signaling pathway.
- The authors also suggest a potentially ingenious use of such Jurkat defects, namely, to use them in reconstitution experiments to validate functionality of a given molecule in a particular pathway.
- Notwithstanding such grave TCR signaling defects, even today hundreds of papers using Jurkat continue to be published annually.
- Use of Jurkat as a model system to study HIV infection in human T cells yields a similarly confusing story, with many discordances in observations between Jurkat and primary CD4 T cells ( ).
Microbial Contamination. A 2008 study reported a batch of Jurkat cells to be contaminated with a retrovirus belonging to the family of( ). Today this virus is designated as or XMLV. Note that this study sourced its Jurkat from (ATCC), a major global supplier of cell lines. Open questions remain,
- Given ATCC’s Jurkat was found to be contaminated with XMLV in 2008, how many previous published studies on Jurkat used such contaminated cells?
- Are Jurkats stored in other cell bank repositories and maintained by labs around the world similarly infected?
- When did Jurkat become infected? In the 1990s when the XMLV is suspected to have arisen during xenograft studies or later?
- How does this infection influence historical results from Jurkat? Clearly, comparisons of ‘clean’ and ‘contaminated’ Jurkats are needed to figure out if and what effect this has on their TCR signaling.
1. Abraham, Robert T., and Arthur Weiss. “Jurkat T cells and development of the T-cell receptor signalling paradigm.” Nature Reviews Immunology 4.4 (2004): 301-308.
2. Schneider, Ulrich, Hans‐Ulrich Schwenk, and Georg Bornkamm. “Characterization of EBV‐genome negative “null” and “T” cell lines derived from children with acute lymphoblastic leukemia and leukemic transformed non‐Hodgkin lymphoma.” International journal of cancer 19.5 (1977): 621-626.
3. Gioia, Louis, et al. “A Genome-wide Survey of Mutations in the Jurkat Cell Line.” bioRxiv (2017): 118117.
4. Markle, Tristan J., Philip Mwimanzi, and Mark A. Brockman. “HIV-1 Nef and T-cell activation: a history of contradictions.” Future virology 8.4 (2013): 391-404.
5. Takeuchi, Yasuhiro, Myra O. McClure, and Massimo Pizzato. “Identification of gammaretroviruses constitutively released from cell lines used for human immunodeficiency virus research.” Journal of virology 82.24 (2008): 12585-12588.