Intermediate steps in positive selection: differentiation of CD4+8int TCRint thymocytes into CD4-8+TCRhi thymocytes.

Abstract

SummaryThe differentiation potential of putative intermediates between CD4 + 8 + thymocytes and mature T cells has been examined. Such intermediate populations were sorted, in parallel with CD4 § 8 + thymocytes, from three types of C57BL/6 mice: major histocompatibility complex (MHC) class II-deficient mice, mice transgenic for an o~/~ T cell receptor (TCR) restricted by class I MHC and normal mice. The sorted populations were then transferred into the thymus of nonirradiated C57BL/Ka mice differing in Thy 1 allotype, and the progeny of the transferred cells were analyzed 2 d later. Surprisingly, with all three types of donor mice, a major proportion of the CD4 + 8~'TCRint-derived progeny were found to be CD4-8 + TCR ~ cells, thus delineating a new alternative pathway for development of the CD8 lineage. In contrast, the transfer of CD4int8 + TCR int thymocytes produced CD4-8 + TCR hi cells but no significant proportion of CD4+8-TCR hi cells, suggesting that there is no equivalent alternative pathway for the CD4 lineage. The results negate some of the evidence for a stochastic/selective model of lineage commitment, and point to an asymmetry in the steps leading to CD4-8 § versus CD4 + 8-T cells.M ature T lymphocytes can be divided into two subpopulations based on their expression of the coreceptor molecules CD4 and CD8. Both populations recognize antigens in the form of peptides presented by MHC molecules. In general, CD4-8 + T cells recognize antigens presented on class I MHC, whereas CD4 + 8-T cells recognize antigens presented on class II MHC. This recognition process involves both an antigen-specific interaction between the TCR and the peptide-MHC complex (1) and an interaction between the coreceptor, either CD4 or CD8, and a conserved region of the same MHC molecule, class II or class I, respectively (for a review see reference 2).Both CD4-8 + and CD4+8 -T cells develop within the thymus from a common CD4 + 8 + TCR 1~ cortical thymocyte population, which itself arises by a developmental process involving successive rearrangements of TCtL c~ and/3 genes (for reviews see references 3 and 4). CD4 + 8 +TCR l~ thymocytes appear destined to die unless they receive a selective set of signals that involve interaction of the TCR and either CD4 or CD8 with peptide-MHC complexes expressed by the thymic stroma. The overall result is the upregulation of TCR, the downregulation of either CD4 or CD8, and the rescue of the celt from programmed death. The entire process, which dictates the antigen specificity and the MHC restriction of the emerging T cell populations, is termed positive selection (5).The precise sequence of events that occurs during positive selection has not been elucidated, but two different models, known as the "instructive" and the "stochastic/selective" models, have dominated the discussion about mechanisms of positive selection. In the instructive model, engagement of MHC class I gives the uncommitted CD4 § 8 + thymocyte a positive selection signal that at the same time also instructs the thymocyte to ...

HD mice: A novel mouse mutant with a specific defect in the generation of CD4+T cells

“…We postulate that the blockade does not affect positive selection of class II-restricted thymocytes but rather a subsequent lineage-commitment step. As mentioned above the transition from the DP to the SP stages is not a simple one-step process, but rather involves progression through a number of intermediate stages defined by different relative levels of surface expression of the CD4 and CD8 molecules (4, 6-8; see (4,(6)(7)(8). It has been proposed that further maturation is not automatic for these cells, but rather requires a specific selective signal (2).…”

“…Recent studies have shown that progression from the DP to the SP stage is marked by passage through a series of transitional stages characterized by intermediate levels of CD4 and CD8 expression (4,(6)(7)(8) (4,8). There is compelling evidence that the DP to SP transition is a multistep process requiring repeated or continual stimuli (11,12).…”

The Quantity of TCR Signal Determines Positive Selection and Lineage Commitment of T Cells

“…Analysis of coreceptor transitional cells in vivo (36) and in vitro (37) revealed that CD4 ϩ CD8 low population is composed of a mixture of CD4-committed and CD8-committed thymocytes, whereas the CD4 low CD8 ϩ population exclusively consists of CD8-committed cells. Similar conclusions were reached using a coreceptor re-expression assay (13).…”

An active CD8α/pMHCI interaction is required for CD8 single positive thymocyte differentiation

“…The CD4 1 CD8b lo TCR hi R2 population is at a transitional differentiation state, which lies between immature DP (R1) and mature SP (CD4 or CD8) thymocytes (R4 or R3, respectively). Transitional cells are characterized by high cell-surface expression of CD69 and CD5 and intermediate-to-high surface levels of TCR and CD3 [11][12][13][14]. We found that only about one seventh of this population of the Tg R2 cells (''B'' population, Fig.…”

“…Such enhancement of antigen recognition is critical not only for triggering the activation of CD8 1 T cells but also for the differentiation of CD8 1 T cells in thymus [4][5][6][7][8][9][10]. Development of CD8 1 T cells in thymus starts with the differentiation of CD4 À CD8 À double negative (DN) precursor T cells into CD4 1 CD8 1 double positive (DP) cells, then into CD4 1 CD8b lo transition cells, and finally maturation into CD8 1 single positive (SP) cells [11][12][13][14]. After emigration into periphery, these CD8 1 T cells, in response to viral infection, can be activated by viral antigens and expanded as effector cytotoxic T lymphocytes, which are capable of eliminating the virus-infected cells [15].…”