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That contrary to dogma, pregnant women and newborns aren’t immunosuppressed or immunodeficient. Rather, in each, immune response is being carefully, exquisitely modulated to ensure maximal protection with minimal damage during unique physiological stages of life that stretch to the limit the immune system’s capacity to balance its propensity for help versus harm. Dogma came into existence and persists because we used bodies other than pregnant or newborn to define what a ‘normal’ immune response is. Classic apple versus orange, these dogmas will persist as long as we continue examining pregnancy and newborn immune responses through such a distorting prism.

That study of microbiota will surely fundamentally change how we think the immune system functions. 10 years ago, who could have predicted an immunotherapy designed to lift the brakes on T cells would depend on presence of specific microbes in the GI tract to help eliminate tumors ranging from sarcomas to melanomas to colon cancer? And yet that’s what two mouse model studies just showed (1, 2). Begs the question is there any immune response our microbiota aren’t involved in? From allergies to autoimmunity to tumors, we are only beginning to appreciate how our microbiota are enmeshed in every aspect of our immune function.

That there’s tremendous, unanticipated redundancy in the immune system. Why unanticipated? Starting in the 1990s, gene mutations/knockouts became the mainstay for figuring out their function. Create a mouse with a gene mutated/knocked out and see what happens. Doing this for genes critical for immune system development and/or function suggested non-redundant functions for genes ranging from MYD88 to Toll-like receptor to Interleukin-1 receptor-associated kinase. Is the same true in humans? On the contrary, tremendous redundancy appears to be the norm (see table below from 3).

The truism that mouse biology doesn’t recapitulate human biology is the more trivial take home message here. More profound is the realization that what we currently know about the immune system is much more likely just the proverbial tip of the iceberg. This brings us directly to the last fascinating bit on this list.

That we don’t even know all the players in the immune system yet. 10 or 15 years ago ask an immunologist about ‘in-betweeners’, cells with some qualities of innate immune cells and some of adaptive, and they’d likely have listed no more than Natural killer cell, Gamma delta T cell, Natural killer T cell. Last few years, the list is growing almost yearly (4, 5). Examples such as Mucosal associated invariant T cell or  Innate lymphoid cell, innate response activator B cells to name a few. They recognize a wider variety of molecules ranging from lipids to microbial vitamin metabolites. Does each tissue and organ harbor an unique subset of such ‘in-betweeners’? What are their functions? Are they part of just the first line of defense where they reside? Or do they liaise, their job to instruct the incoming T and B cells what they should or shouldn’t do? ‘You’re in the gut, you can’t do that here, help push out some more IgA instead‘. ‘You’re in the skin, help bring some more macrophages here stat‘. Do they help in immune memory formation? Do they help immune memory cells reside in the sites that induced their formation? More questions than answers at present.


1. Vétizou, Marie, et al. “Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota.” Science 350.6264 (2015): 1079-1084. http://www.ncbi.nlm.nih.gov/pmc/…

2. Sivan, Ayelet, et al. “Commensal Bifidobacterium promotes antitumor immunity and facilitates anti–PD-L1 efficacy.” Science 350.6264 (2015): 1084-1089. https://www.researchgate.net/pro…

3. Casanova, Jean-Laurent. “Severe infectious diseases of childhood as monogenic inborn errors of immunity.” Proceedings of the National Academy of Sciences 112.51 (2015): E7128-E7137. http://www.pnas.org/content/112/…

4. Godfrey, Dale I., et al. “The burgeoning family of unconventional T cells.” Nature immunology 16.11 (2015): 1114-1123.

5. Riera Romo, Mario, Dayana Pérez‐Martínez, and Camila Castillo Ferrer. “Innate immunity in vertebrates: an overview.” Immunology (2016).