What is immunocompetence? Seems like a simple enough question. In the past, we would have said, “That’s easy. T cells and B cells, of course”. Then along came a pantheon of innate immunocytes (dendritic cells, macrophages, NK cells, NK T cells to name a few), and the concept of immunocompetence expanded to include them. While traditional understanding of immune responses accorded major decision making powers to T and B cells, our newer expanded understanding accords considerable influence to these innate immunocytes. However, we have yet to take a critical conceptual step forward.

In particular, for the most part, we continue to consider tissues and organs to be passive players in immune responses. Instead, we accord to the innate (dendritic cells, macrophages, etc.) and adaptive (T and B cells) elements of the immune system the capacity to orchestrate an immune response from beginning to end. In response to alarm, we imagine that the tissue-resident dendritic cells are activated, that they mobilize and migrate towards the draining lymph node(s) where they engage with and activate antigen-specific T cells, which then orchestrate the rest of the immune response to resolve the alarm and re-establish homeostasis.  Of course, this scenario is not purely hypothetical: we do have an abundance of supporting experimental studies. Yet, is not this tapestry stitched according to our preconceived notions of what constitutes an immune response? Whither the tissue itself amidst the tumult of an immune response?

If we attend to the poor tissue at all, we imagine it doing its part in initiating the alarm and then passively waiting for the immune system to resolve the problem. On the other hand, if we accorded the property of immunocompetence to every cell in the body, we could perhaps perceive immune responses rather differently. Imagine if every cell in the body were immunologically competent, capable of not only responding to and communicating alarm to its neighbors and to immunocytes but also capable of actively participating in and regulating immune responses. Such a scenario would upend our current understanding of immune responses.

Imagine now, in health, a tissue in intimate contact with its environs, selectively welcoming the mobile elements of the traditional immune system to come and reside within it. Among others, these would be the progenitors of the tissue-resident dendritic cells and macrophages coming in and settling down to life within its environs, bathed in its unique interstitial fluids. Let’s imagine that this tissue’s unique immunological identity would ensue from its unique composition, embellished in its unique fashion with various elements of the immune system, and from its unique function. This would be why the anterior chamber of the eye and the seminal fluid would be rich in TGF-beta, while the liver would have an excellent capacity to regenerate. When an alarm is initiated within this tissue, instead of sitting passively in its immobility, we could instead imagine the events constituting an immune response differently.

This tissue with its unique composition and unique function, would it not respond in its unique fashion to a given alarm? Would it sit passively in wait while its tissue-resident dendritic cells mobilized towards the draining lymph node(s) to elicit T cells towards it? This tissue has spent its entire life assuming its identity, growing and developing and changing with time, performing its unique function, and responding to changes in its environment. When any change in its homeostasis necessitated an immune response involving this tissue, why would it not respond in a manner unique to itself?

If we agree that it makes sense for a given tissue to have unique structure and function, is it not reasonable to assume that it could also sound alarm in response to unique cues, have unique modes to communicate such alarm, and have unique approaches to elicit, control and resolve immune responses that occur within it? In its moment of trouble, when it and its body’s very existence may be in question, is it reasonable to assume that a tissue would cede its raison d’etre to immunocytes? Yet, this is how we have tacitly envisaged immune responses. Why do we not conceptually accord greater decision-making powers in immune responses to tissues and organs? If we did so, we may improve our understanding of what constitutes an appropriate and adequate immune response at a particular site, better understand the immunological strengths and vulnerabilities of different tissues and organs, and be able to design more effective vaccines and immunotherapies.

Post by Tirumalai Kamala:

Tissues and Immunity: Let No Human Put Asunder What Nature Put Together

Tissues and Immunity: Let No Human Put Asunder What Nature Put Together