The Battle of Evermore

Antigen Presentation: The first in a series of basic concepts in Immunology

Recognition of a pathogen as a pathogen is one of the most fundamental functions of the immune system. The immune system can be divided into two basic classes, partly based on the ways in which pathogens are recognized: the innate and the adaptive, or acquired, immune system. The innate immune system is the early arm of the immune system, acting rapidly, within minutes of encountering a pathogen. Innate immunity is inherently broad in its specificity—cells of the innate immune system broadly recognize pathogens as pathogens, not specifically as X virus of Y bacteria. This is not to say that innate immunity is indiscriminate, far from it. The way in which innate immune cells recognize microbes tends to identify whole classes of pathogens, labeling a microbe generally as “gram-negative bacterium” instead of specifically “E. coli”. That is not the whole story, and will be the subject of another exposition another day.

What I want to discuss today are some of the ways in which the adaptive immune system sees pathogens. There two principal types of cells that constitute the adaptive immune system are antigen presenting cells and effector cells. (Though these distinctions are not hard and fast, some APCs are effectors and vice versa.) Antigen presenting cells, affectionately called APCs, “present” antigens to effector cells. What does this mean?

Starting with the effector cells, in this case T cells (see sidebar). T cells express an antigen receptor called the T cell receptor (TCR) that recognizes protein antigens presented to them by APCs. Once T cells recognize antigens, they react in a variety of ways: cytotoxic (literally: toxic to cells) T cells (CTLs) kill the cells that present the antigen to them, while helper T cells (TH cells) produce cytokines (see earlier) that communicate with other cells. Given that antigen recognition by a T cell can have powerful and far-reaching consequences, it is evident that it should be a tightly controlled process. And tightly controlled it is—by two elegant little biological caveats.

The first is that TCRs only recognize small fragments of said protein antigens called peptides, usually between 8 and 15 amino acids in length. T cells are very picky about the length and nature of these peptides, and APCs therefore have to “process” whole proteins down into the precise fragments the TCR can see. This process of degradation usually happens only inside a cell and requires the cell to have a fairly extensive and specialized “antigen processing” machinery. So not just any cell can present antigens to T cells, and the ones that can, cannot present just any antigen.

The second is that TCRs can only see peptides when they are carried on the surface of the APC on specific carrier proteins called MHC molecules. MHC expands into major histocompatibility complex (and I am violating every canon of science writing that says you have to define your term before you use an abbreviation, but the expansion only clouds the issue here), and refers to a set of genes that encode proteins that present antigens, called antigen presenting molecules. Something I won’t go into now is that these MHC genes are what determine whether organs are compatible (histo means tissue) for transplants, they are called HLA molecules in human, HLA typing anyone? Anyway, the function of MHC molecules is to carry peptides and present them to T cells. This is particularly nifty because T cells are restricted to recognizing only the antigens presented to them by self-MHC, which basically says that the T cells in my body only recognize antigens presented on the MHC molecules my body has.

So a T cell is constrained to recognize antigens only in a certain form, and then only when self-MHC molecules present those antigens. MHC molecules fall into two classes (of course, its not that simple, but its broadly true), MHC class I and class II. MHC class I molecules present peptide antigens that are made inside the cell and MHC class II those that are swallowed from outside the cell. Cells only make proteins from a microbe when they are infected by that microbe, and MHC class I molecules signal that a cell is infected by presenting the microbial protein as an antigen. The best way to deal with an infected cell in to destroy it, and cytotoxic T cells see antigens presented by MHC class I and kill the cells that present them the antigen. MHC class II molecules on the other hand present antigens from proteins they find floating around outside the cell, to helper T cells. Microbial proteins floating around indicate that there in an infection somewhere around, not necessarily in the cell that is presenting the antigen. So when helper T cells see their antigens on MHC class II, they don’t kill the messenger, but send out cytokine summons to all other immune cells to come a-hunting for the infection in the area.

Thus does antigen presentation form a critical part of immune recognition, battling on evermore in the standoff between bugs that don’t want to be recognized and bodies that want to recognize and eliminate them. The evolution and function of antigen presentation is an absorbing and continuous field of study, and has lead to some fascinating insight into the ways in which cells organize their insides. Some other areas that continue to interest are the sources of various antigens, and the ways in which T cells are educated to recognize foreign antigens but not the body itself. While antigen presentation is the most basic platform of immune recognition, it is also the jumping off point for some truly awesome research. Coming up in future posts…