T‐cell system is conventionally regarded as an enabler of diverse compartments, which correspond to different steps of differentiation and functional subsets of mature cells taking part in the immune response in the peripheral lymphoid and non‐lymphoid tissues.
In this chapter, we give a overview of the T‐cell system, more functionally than anatomically oriented, to reflect its extreme plasticity. This plasticity is thought to lie at the heart of the diversity of T‐cell malignancies now recognized by the World Health Organization.
General View of the Differentiation and Function of T Lymphocytes
The immune system can be classified into two basic component: (i) the innate immune system, and (ii) the acquired immune system. The innate immune system is considered to be relatively agnostic to any specific antigen, and is often described as invariant. The innate immune response is the first line of defense, and typically exhibits limited specificity. Examples of innate immune response may include phagocytosis by macrophages, barriers to infection provided by the skin and tears, natural killer and mast cells, and complement‐mediated cytolysis. In contrast, the adaptive (or sometimes called acquired) immune response develops in response to specific antigen, being “custom” designed for the antigen in question. It usually occurs later in the immune response, and has the ability to recall the response to past infections. Components of a functioning acquired immune response might involve antigen‐presenting cells presenting antigen or T cells, the activation of specific T cells which would signal to B cells enlisting their engagement in the response and the production of highly specific antibody capable of binding specific antigen. T and B lymphocytes are the major types of lymphocytes found in the human body, where they can constitute 20–40% of all white blood cells, with only about 2–3% being found in the peripheral circulation, the remainder being localized to various lymphoid organs (lymph nodes, spleen, submucosal tissue). Remarkably, the total mass of lymphocytes in the body can approximate the mass of the brain and liver.
As shown in Figure 1.1 [1], T lymphocytes arise from a bone marrow precursor, which undergoes maturation and functional orientation in the thymus. Antigen‐specific T cells mature in the thymic cortex, where the elements recognizing self‐peptides and major histocompatibility antigens expressed by cortical epithelial cells and thymic nurse cells are eliminated via apoptosis. Failure to eliminate those T cells recognizing self‐peptides is thought to give rise to a host of autoimmune disorders.
Figure 1.1 Schematic overview of T‐cell ontogeny and differentiative trajectories.
Source: Claudio Tripodo, Stefano Pilleri.
Cortical thymocytes exhibit an immature T‐cell phenotype and express a characteristic repertoire of proteins including TdT, CD1a, CD3, CD5, and CD7. CD3 is expressed in the cytoplasm until completion of T‐cell receptor (TCR) gene rearrangement and is then exported to the cell membrane. Cortical thymocytes are initially CD4/CD8 double negative.
Medullary thymocytes exhibit a phenotype similar to that of mature T cells of the peripheral lymphoid organs with segregation of CD4 and CD8 antigens. Based on the structure of the variable portion of the TCR, T cells have been divided into two classes, including alpha/beta and gamma/delta T cells. They are both associated with the CD3 complex, which contains gamma, delta, and epsilon chains. Gamma and delta T cells usually lack expression of CD4, CD8, and CD5, although a subpopulation can expresses CD8. They represent less than 5% of normal T lymphocytes and are primarily located in the splenic red pulp, intestinal epithelium, and other epithelial sites. They also have a restricted range of antigen recognition and take part in the innate immune reaction, serving as a first line of defense against bacterial peptides. They are often involved in responses to mycobacterial infections and in mucosal immunity. T lymphocytes of the adaptive immune system, which are heterogeneous and functionally complex, include naïve, effector (regulatory and cytotoxic), and memory T cells.
CD4+ T cells are primarily regulatory in nature. Based on their cytokine secretion profiles, they are divided into two major types: T helper (Th) 1 cells and Th2 cells. Th1 cells secrete interleukin (IL) 2 and interferon gamma, while Th2 cells secrete IL4, IL5, IL6, and IL10. Th1 cells provide help mainly to other T cells and macrophages, whereas Th2 cells provide help mainly to B cells in antibody production. CD4+ T cells can both help and suppress immune responses and consist of multiple subpopulations. Recent studies have shown overexpression of the transcription factors TBX21 (also known as T‐bet) and GATA3 in Th1 and Th2 lymphocytes, respectively.
T regulatory (Treg) cells suppress immune responses to cancer and limit inflammatory responses in tissues. These CD4‐positive cells, which are thought to play an important role in preventing autoimmunity, express a high density CD25 and the transcription factor FOXP3. Th17 lymphocytes correspond to a subset of CD4+ effector T cells, characterized by expression of the IL17 family of cytokines, and play a role in immune‐mediated inflammatory diseases and other conditions. Recently, there has been a rapidly evolving literature around a unique CD4+ T‐cell subset that takes part in the natural functions of normal germinal centers. These cells, called T follicular helper (Tfh) cells, support B cells in the context of the germinal center reaction. They reveal a distinctive phenotype with expression of the germinal center markers BCL6 and CD10 together with CD57, ICOS and CD279/PD1 and produce the chemokine CXCL13 as well as its receptor CXCR5. CXCL13 causes proliferation of follicular dendritic cells and facilitates the migration of B and T lymphocytes expressing CXCR5 into the germinal center.
The T‐cell System as a Frame for Peripheral T‐cell Lymphoma: Taking Plasticity into Account
The mature T‐cell system consists of different subsets of lymphoid T cells variably trafficking between peripheral blood, lymphoid, and peripheral tissues. These cells display diversified functional phenotypes, participating in immune responses as effectors or though the orchestration of other immune cellular and non‐cellular contributors.
This gross distinction also implies that one major branch of the T‐cell functional differentiation tree displays transcriptional and synthetic machineries allowing cytotoxic effector functions, including for example EOMES transcription factor expression, granzymes, perforins, and key proinflammatory cytokines such as TNFα and interferon gamma (IFN‐γ). Another major branch is strictly bound, in its activity, to microenvironmental clues of the immune contexture.
In this regard, the described differentiated phenotypes of CD4+ Th‐cell subsets are known to include Th1 and Th2 clusters identified by the activity of T‐bet and GATA3 transcription factors [2]; the Th17 and Th22 clusters driven by RORC1 transcriptional regulation [3, 4]; the FOXO1 and interferon regulatory factor 4 (IRF4) controlled Th9 cluster [5]; the Tfh cluster, which is dependent upon BCL6 and TOX2 activity [6], and the regulatory T‐cell cluster associated with FOXP3 [7]. This repertoire of discrete and differentiated cells imparts a considerable degree of plasticity to the immune system, enabling it to respond potently with high selectivity.
Th subsets of CD4 positive cells are defined by the activity of selected transcription factors, including diversified signal transducers and activators of transcription (STAT) family members, whose signaling and preferential synthesis of specific cytokines, may respond to polarizing stimuli from the surrounding environment by reshaping their phenotypic differentiation, eventually undergoing conversion to a different functional subset [8, 9]. Specific cytokines that characterize most of the pathogen‐associated or sterile inflammatory responses, such as IL6, TNFα, and IL12 may drive Th cell polarization toward Th1 (STAT4‐dominant), Tfh, Th17, or Th22 fates (all three STAT3‐dominant), according to their relative abundance and association with other regulatory cytokines such as IL1b, IL21, and IL23 [8]. Similarly, the pleiotropic cytokine transforming growth factor beta is involved in the induction and/or conversion of Treg (STAT5‐dominant), Th2 and Th9 (both STAT6‐dominant) in combination with other polarizing cytokines such