Selection of self-reactive T cells in the thymus

Abstract

On the whole, the healthy adaptive immune system is responsive to foreign antigens and tolerant to self. However, many individual lymphocytes have, and even require, substantial self-reactivity for their particular functions in immunity. In this review, we discuss several populations of lymphocytes that are thought to experience agonist stimulation through the T cell receptor during selection: nTreg cells, iNKT cells, nIELs, and nTh17s. We discuss the nature of this self-reactivity, how it compares with conventional T cells, and why it is important for overall immune health. We also outline molecular pathways unique to each lineage and consider possible commonalities to their development and survival.

Figure 1. Proposed agonist selection of unique subsets of TCRαβ + T cells in the thymus

The thymus generates a large pool of immature thymocyte progenitors that express clonally distinct αβ TCRs (DP). The reactivity of these TCRs for self-MHC ligands (shown by color scale, darker green being more reactive) plays a defining role in fate. Cells that do not express a TCR, or express a TCR with no ability to react with thymic ligands will die by neglect. Those with low affinity undergo positive selection to become CD4+ helper or CD8+ killer cells and the major cellular products of the thymus. Those with high affinity undergo clonal deletion to preserve self-tolerance. However, several smaller sub-populations of lymphocytes also develop in the thymus: the precursors to CD8αα+ intraepithelial lymphocytes (nIELp), invariant NK T cells (iNKT), natural FoxP3+ regulatory T cells (nTreg) and natural T helper cells that can produce IL-17 (nTh17). Evidence summarized in this review suggests that these four subsets experience stronger interactions with self-ligands during development (agonist selection). Each of these subsets requires distinct molecular factors (some of which are listed). They arise at distinct stages; can be Class I, Class II, or CD1d restricted; and can express either or no co-receptor. However, their commonalities include: 1) an activated/memory phenotype, 2) evidence for stimulation by high affinity (agonist) self-ligands during development, 3) a requirement for TGFβ, and 4) regulatory function in immunity.

Figure 2. Cross talk between developing iNKT and CD8SP progenitors in the thymus generates innate CD8 T cells

The iNKT, CD4 helper and CD8 killer lineages normally develop largely independently (WT, left panel). However, in some gene deficient or mutant mice (ITK, KLF2, CDP, Id3, and SLP76Y145F) (KO, right panel) and in some inbred strains (like BALB/c), iNKT cells that constitutively produce IL-4 are expanded. IL-4 acts on developing CD8 lineage cells to upregulate the transcription factor eomes and a number of downstream target genes. This leads to the generation of CD8 T cells with a memory phenotype and capacity to rapidly produce cytokines.

Figure 3. Unique aspects of nTreg cell development in the thymus

A) A double positive (DP) progenitor is positively selected upon interacting with peptides presented by cortical epithelial cells. In this model, we propose that nTreg and conventional T cells are selected in a similar manner in the cortex, i.e. via low affinity interactions with abundant self-peptides. A given clone might recognize multiple distinct self-peptides in this affinity range. B) After positive selection, progenitors migrate from the cortex to medulla and differentiate to the semi-mature (HSA^hi, CD62L^lo) stage. If a progenitor encounters self-peptides displayed by B7.1/2+ medullary APC (mTEC or DC) with high affinity, this triggers the upregulation of CD25. C) A CD25+ Foxp3− nTreg cell precursors requires IL-2 for survival and differentiation to the mature Foxp3+ nTreg cell stage. D) Mature, self-reactive nTreg cells emigrate from the thymus to populate the peripheral lymphoid organs. E) In the periphery, nTreg cells continue to perceive higher affinity self-ligands (presumably same or similar to peptide B) and regulate self-tolerance in the steady state.

Figure 4. Unique aspects of iNKT cell development in the thymus

A) iNKT cells arise from rare DP progenitors that express a Vα14-Jα18 TCR. Interaction with hematopoetic APC (DP cells) that express CD1d molecules and stimulatory self-lipids, facilitated by SLAM family member interactions, initiate positive selection through the src family kinase fyn. B) The earliest post-selection iNKT cell is an HSA^hi “stage 0” cell, which already express the iNKT lineage transcription factor PLZF. As the progenitor develops, it downregulates HSA (stage 1), and upregulates CD44 (stage 2). C) During this time it undergoes cellular proliferation requiring cMyc. The cellular interactions that iNKT cells make in the medulla are not well characterized, but CD28 interaction with B7.1/2+ APC is required for iNKT cell expansion. D) Stage 2 iNKT cells upregulate Tbet and respond to IL-15. The most mature (stage 3) iNKT cell expresses NK1.1 and is retained in the thymus for long periods. E) Alternatively, stage 2 iNKT cells can emigrate from the thymus and populate the spleen and liver. Some evidence suggests that peripheral iNKT cells do not continuously perceive stimulatory self-lipid. Rather, APC can be activated during infection to display stimulatory self-lipids and thus activate iNKT cells.