Immunology & Cell Biology最新文献

The clinical development of Natural Killer (NK) cell-mediated immunotherapy marks a milestone in the development of new cancer therapies and has gained traction due to the intrinsic ability of the NK cell to target and kill tumor cells. To fully harness the tumor killing ability of NK cells, we need to improve NK cell persistence and to overcome suppression of NK cell activation in the tumor microenvironment. The trans-membrane, protein tyrosine phosphatase CD45, regulates NK cell homeostasis, with the genetic loss of CD45 in mice resulting in increased numbers of mature NK cells. This suggests that CD45-deficient NK cells might display enhanced persistence following adoptive transfer. However, we demonstrate here that adoptive transfer of CD45-deficiency did not enhance NK cell persistence in mice, and instead, the homeostatic disturbance of NK cells in CD45-deficient mice stemmed from a developmental defect in the progenitor population. The enhanced maturation within the CD45-deficient NK cell compartment was intrinsic to the NK cell lineage, and independent of the developmental defect. CD45 is not a conventional immune checkpoint candidate, as systemic loss is detrimental to T and B cell development, compromising the adaptive immune system. Nonetheless, this study suggests that inhibition of CD45 in progenitor or stem cell populations may improve the yield of in vitro generated NK cells for adoptive therapy.

Over time I have recognized the value of my unique journey through science, from academia to industry, and I encourage others to appreciate how their own unique experiences shape the scientists we become. This article describes this journey.

In July 1999, I took my final curtsey as an aspiring ballet dancer in London. At the time, I was devastated, having been “assessed out” by the ballet school I’d attended the year after I finished high school in Ireland. I wish I knew then what I know now: there are no endings in a career, just different paths. It took a few more iterations for me to learn that lesson. I hope my experience described in this article can provide some reassurance for anyone out there grappling with their next career move.

This year marks the 100th year of the publication of Immunology & Cell Biology since it was first published in March 1924 as the Australian Journal of Experimental Biology and Medical Science. In this Editorial, we recount the journal from its founding, to its focus on immunology, through to the modern era.

Memory T cells are generated from naïve precursors undergoing proliferation during the initial immune response. Both naïve and memory T cells are maintained in a resting, quiescent state and respond to activation with a controlled proliferative burst and differentiation into effector cells. This similarity in the maintenance and response dynamics points to the preservation of key cellular fate programs; however, whether memory T cells have acquired intrinsic changes in these programs that may contribute to the enhanced immune protection in a recall response is not fully understood. Here we used a quantitative model–based analysis of proliferation and survival kinetics of in vitro–stimulated murine naïve and memory CD8⁺ T cells in response to homeostatic and activating signals to establish intrinsic similarities or differences within these cell types. We show that resting memory T cells display heightened sensitivity to homeostatic cytokines, responding to interleukin (IL)-2 in addition to IL-7 and IL-15. The proliferative response to αCD3 was equal in size and kinetics, demonstrating that memory T cells undergo the same controlled division burst and automated return to quiescence as naïve T cells. However, perhaps surprisingly, we observed reduced expansion of αCD3-stimulated memory T cells in response to activating signals αCD28 and IL-2 compared with naïve T cells. Overall, we demonstrate that although sensitivities to cytokine and costimulatory signals have shifted, fate programs regulating the scale of the division burst are conserved in memory T cells.

Human leukocyte antigen (HLA) class I molecules have been shown to influence the immune response to HIV infection and acquired immunodeficiency syndrome progression. Polymorphisms within the HLA-B35 molecules divide the family into two groups, namely, Px and PY. The Px group is associated with deleterious effects and accelerated disease progression in HIV⁺ patients, whereas the PY group is not. The classification is based on the preferential binding of a tyrosine at the C-terminal part of the peptide in the PY group, and a nontyrosine residue in the Px group. However, there is a lack of knowledge on the molecular differences between the two groups. Here, we have investigated three HLA-B35 molecules, namely, HLA-B*35:01 (PY), HLA-B*35:03 (Px) and HLA-B*35:05 (unclassified). We selected an HIV-derived peptide, NY9, and demonstrated that it can trigger a polyfunctional CD8⁺ T-cell response in HLA-B*35:01⁺/HIV⁺ patients. We determined that in the complex with the NY9 peptide, the PY molecule was more stable than the Px molecule. We solved the crystal structures of the three HLA molecules in complex with the NY9 peptide, and structural similarities with HLA-B*35:01 would classify the HLA-B*35:05 within the PY group. Interestingly, we found that HLA-B*35:05 can also bind a small molecule in its cleft, suggesting that small drugs could bind as well.

Laboratory science sometimes looks like it's built exclusively for young people, but if you look closely, you’ll find another group of scientists waiting to join your lab: those of us who didn’t quite launch our careers on a normal trajectory. Welcoming a second-career scientist into your lab takes time and resources, but may just be well worth it. Here's what one second-career scientist wants you to know about supporting second careers in immunology.

It is now 60 years since Ian Mackay and Macfarlane Burnet published their seminal text “The Autoimmune Diseases” in which they examined the full scope of human inflammatory pathology as a manifestation of the underlying structure and function of the immune system. Here I revisit this approach to ask to what extent has the promise of Mackay and Burnet's work been exploited in clinical medicine as currently practiced. In other words, is immunology doing well? Despite spectacular headline contributions of immunology in clinical medicine, I present evidence suggesting a performance ceiling in our capacity to answer the relatively straightforward questions that patients frequently ask about their own diseases and find that this ceiling exists across almost all of the 100 immune-mediated inflammatory diseases examined. I propose that these questions are difficult, not so much because the immune system is overwhelmingly complex but rather that we have more to learn about the relatively simple agents and rules that may underpin self-organizing complex interacting systems as revealed in studies from other disciplines. The way that the immune system has evolved to exploit the ancient machinery determining three independent cell fate timers as described in this Journal would be a great place to start to decode the self-organizing principles that underpin the emergent pathology that we observe in the clinic.

The human pathogen Streptococcus pyogenes, or Group A Streptococcus (GAS), is associated with a variety of diseases ranging from mild skin and soft tissue infections to invasive diseases and immune sequelae such as rheumatic heart disease. We have recently reported that one of the virulence factors of this pathogen, the pilus, has inflammatory properties and strongly stimulates the innate immune system. Here we used a range of nonpathogenic Lactococcus lactis gain-of-function mutants, each expressing one of the major pilus types of GAS, to compare the immune responses generated by various types of fully assembled pili. In vitro assays indicated variability in the inflammatory response induced by different pili, with the fibronectin-binding, collagen-binding, T antigen (FCT)-1-type pilus from GAS serotype M6/T6 inducing significantly stronger cytokine secretion than other pili. Furthermore, we established that the same trend of pili-mediated immune response could be modeled in Galleria mellonella larvae, which possess a similar innate immune system to vertebrates. Counterintuitively, across the panel of pili types examined in this study, we observed a negative correlation between the intensity of the immune response demonstrated in our experiments and the disease severity observed clinically in the GAS strains associated with each pilus type. This observation suggests that pili-mediated inflammation is more likely to promote bacterial clearance instead of causing disruptive damages that intensify pathogenesis. This also indicates that pili may not be the main contributor to the inflammatory symptoms seen in GAS diseases. Rather, the immune-potentiating properties of the pilus components could potentially be exploited as a vaccine adjuvant.

In 1943, Australian scientist Miss Dora Lush's life was tragically cut short in her relentless pursuit of scientific knowledge. This article commemorates the 100-year anniversary of the journal, ICB, by celebrating the remarkable career of Lush, a renowned bacteriologist who achieved unparalleled success in an era when women faced formidable barriers to tertiary education and scientific recognition. Graduating with a Master of Science from the University of Melbourne in 1934, Lush's ground-breaking research in infectious diseases, conducted in collaboration with Frank Macfarlane Burnet AO at the Walter and Eliza Hall Institute (WEHI), played a pivotal role in advancing our understanding of viruses, including influenza, herpes and myxomatosis. Lush's pivotal work on influenza provided the foundational evidence to develop the influenza vaccine, a cornerstone of global public health today. Similarly, her investigation of myxoma virus in rabbits, with its potential for pest control and ecological impact, was used to instruct creation of the world's first biological control program against a mammalian pest. Tragically, Dora Lush succumbed to scrub fever in 1943, a disease she contracted during a laboratory accident. Her unwavering commitment to science led her to offer her own blood for research as she battled the infection, exemplifying her dedication to advancing knowledge even in the face of personal adversity. Lush's legacy endures through scholarships and fellowships that bear her name in Australia, fostering the careers of aspiring scientists. Her ground-breaking research and unwavering determination continue to inspire generations, reminding us of the importance of diversity in science and the enduring impact of pioneering women like Lush.