CD4 T cells, we often read, are the orchestrators of immune responses, conducting a host of other cell types within lymphoid and non-lymphoid organs. This presents an image of CD4 T cells as standing somewhat apart from the fray: directing dendritic cells and macrophages; driving on B cells and CD8 T cells towards a cacophonic response of cytokines, proteolytic enzymes and resolvins. Of course, such metaphors only work so far before they fall apart. But the image of the driven, decisive CD4 T cell with a master plan is now far from our current understanding of how adaptive immune responses are initiated, shaped and resolved.
With the discovery of new immune cell types from dendritic cells in the 1970s by Ralph Steinman,1 and the more recent uncovering of innate lymphoid cells, it is becoming increasingly clear that CD4 T cells are players in plastic and co-operative immune responses. From their generation in the thymus to their decision to become memory cells, CD4 T cells are reliant on other immune and somatic cells to inform their decisions. The immune response is a conversation not a dictation.
T cell development: epithelial cells regulate T cell life and death decisions
CD4 T cells live and breathe by their T cell receptors (TCRs), the cell surface molecule that gives them their specificity. TCRs are stitched together during T cell development in the thymus. Without the ability to recognise self-MHC molecules, T cells are blind to the world. Cortical thymic epithelial cells are the cells that focus the TCR repertoire towards self-recognition – as such, they are the first of many cell types that shape the identity of CD4 T cells.
Second in line are medullary thymic epithelial cells. These cells sculpt the TCR repertoire further, whittling out many of the T cells that recognise self-peptides so strongly that they pose a risk to self-tolerance. In collaboration with thymic dendritic cells, and maybe thymic B cells, these epithelial cells are one of the first cell types to dictate directly CD4 T cell function by driving the differentiation of thymic regulatory T cells.
T cell activation is a collaborative and dynamic process
CD4 T cells leave the thymus as resting, inactive cells. This is not to say that they float around, distant from the rest of the immune system. CD4 T cells recirculate through secondary lymphoid organs scanning MHC class II molecules on dendritic cells (DCs) for a peptide that they recognise as their specific antigen. These periodic encounters with self-peptide-MHC II complexes provide survival signals to CD4 T cells.
Interleukin 7, produced by stromal cells, provides additional survival signals to CD4 T cells. Stromal cells play a number of supporting roles for CD4 T cells – not least creating the scaffold over which immune cells migrate. Through the production of chemokines, they also dictate where immune cells reside within secondary lymphoid organs.
It is within the T cell zone of lymph nodes that DCs congregate following migration from peripheral organs. DCs receive pathogen-derived signals that cause upregulation of a vast array of costimulatory molecules, cytokines and chemokines. These matured DCs arrive in lymph nodes ready to inform CD4 T cells of the nature and extent of the infection the host faces. It is this information that CD4 T cells must decode to enable them to make the right decision about their, and the host’s, fate.
…the image of the driven, decisive CD4 T cell with a master plan is now far from our current understanding of how adaptive immune responses are initiated, shaped and resolved.
CD4 T cell priming by DCs involves two main events: proliferation and differentiation. Proliferation ensures that sufficient antigen-specific CD4 T cells are generated to carry out the many jobs for which CD4 T cells are responsible. These different jobs require the activated CD4 T cell to take on new functions that are best suited to deal with the evading pathogen.
Since Tim Mossman and Bob Coffman first described Th1 and Th2 cells in 1986, immunologists have sought to put activated CD4 T cells in discrete boxes. 3Initially based on cytokine production and now, in addition, on cell surface marker and signature transcription factors expression, T cell subsets have proliferated almost as much as activated T cells proliferate! While strong, repeated polarising signals may drive an activated CD4 T cell to differentiate down one particular pathway, the reality of a heterogeneous and unsynchronised immune response in vivo is likely to be more complex.
T cell differentiation – to remain or migrate?
We have a fair understanding of many of the factors that direct CD4 T cell differentiation. Polarising cytokines, made by a range of cell types including DCs, innate lymphoid cells and stromal cells, play a dominant role in this decision. T cell intrinsic factors – especially how well the TCR binds to peptide–MHC II – can also influence the fate of activated T cells as described by Kim Bottomly and colleagues in the late 1990s.3
What is much less clear is how the decision is made about which CD4 T cells remain in the lymph node and which leave to rout out the pathogen at the infection site. In lymph nodes, the conversation between CD4 T cells and B cells, which causes germinal centre formation, is a defining one. Immunologists tend to focus on what B cells get out of this interaction. CD4 T cells may also benefit: work from several investigators, including David Gray,4 indicates that these interactions may promote the survival of activated CD4 T cells into the memory pool.
CD4 T cells that migrate to the infection site must, if they are to contribute to pathogen control, also see their antigen again. These interactions may warn the CD4 T cell that a sustained inflammatory anti-pathogen response is still required. Alternatively, they may prompt the CD4 T cell to instigate a different task, beginning the process of turning down the response, and initiate tissue repair. Some of these CD4 T cells will survive into the memory pool, potentially differentiating into the recently described population of tissue resident memory T cells. These cells remain at infection sites, ready and armed for subsequent infections, a process that will again require the co-operation of an array of immune and stromal cells.
Communication and cooperation are key to successful immune responses
Over the course of their entire life, CD4 T cells receive encouragement and direction from the many and various cells that they encounter. These conversations affect when and how they are activated and whether they survive. CD4 T cells use the information they receive in a flexible and responsive manner rather than one that is prescribed and rigid. CD4 T cells could, therefore, be said to be participants in a structured improvisation rather than the conductors of a pre-defined score.
Centre for Immunobiology, Institute of Infection, Immunity and Inflammation
University of Glasgow
- Steinman RM, Cohn ZA 1973 Journal of Experimental Medicine 137 1142–1162
- Mosmann TR et al. 1986 Journal of Immunology 136 2348–2357
- Constant SL & Bottomly K 1997 Annual Reviews of Immunology 15 297–322
- Barr TA, et al. 2012 Infectious Disorders – Drug Targets 12 222–231