T cell diversity

Patrick writes: "Virginal CD8 T cells encountering MHC-associated antigen will undergo activation, proliferation, gaining effector functions, followed by contraction and the development of central and effector T cell memories. A number of models have been proposed to account for the generation of these T cell subsets. The observation of homeostatic proliferation suggests that virginal CD8 T cells may not have been as naïve as one have previously thought. This proliferation may have given rise to intraclonal diversity and pre-programmed the “naïve” precursors to develop into differing subsets when encountering antigens. An alternative “progressive differentiation” model proposes that different signal strength at the time of priming may give rise to the diverse subsets. An extension of this model is that a stronger signal may impact the differentiation pattern of one naïve T cells encountering antigen on a DC in contrast to two or three naïve T cells encountering the antigen on the same DC. A “latecomer effect”, i.e., a naïve T cell encountering the antigen late, also may drive the development of long-living T cells.

In this report (Immunity. 2007 Dec 21;27(6):985-997), Stemberger et al. developed a single cell adoptive transfer system to show one CD8+ CD45+ naïve T cell can give rise to diverse phenotypic subsets with functionality (as measured by degranulation, IL-2, IFNg and TNFα expression), including T effectors (CD127-lo, CD62L-lo); effector memory T cells (CD127-hi, CD62L-lo); and, central memory T cells (CD127-hi, CD62L-hi). The observed phenotypic and functional patterns of these subsets are comparable to those seen in resident CD8+ CD45+ T cells upon antigen activation. This in vivo assay, while technically challenging, may provide a handle to study the factors that promote the differentiation and development of effector and central memories."
Stemberger et al. Immunity. 2007 Dec 21;27(6):985-997. A Single Naive CD8(+) T Cell Precursor Can Develop into Diverse Effector and Memory Subsets.

T cell diversity: E Unum Pluribus

Infections stimulate the expansion of a few individual progenitor T lymphocytes, perhaps as few as 50, into millions of specific T lymphocytes (Review). These T cell clones are typically diverse, encompassing subsets of short-lived effector cells, long-lived memory cells, and a variety of intermediate subsets. The proposed models of diversification focus on the priming phase because previous observations have shown that an initial, transient encounter with antigen suffices to induce protracted proliferation and complete subset diversity. Differentiation capabilities might be predetermined, with the naive precursor cells programmed to undergo diversification into all subsets. Alternatively, a ‘‘progressive differentiation’’ model proposes that the strength of antigen stimulation and costimulation at priming determines how far the T cell progeny are driven along a differentiation spectrum.

Here, the ability of precursor T cells to differentiate into multiple subsets was tested by transferring a single naive T cell and then analyzing its progeny after immunization. Twelve days after transfer and immunization of the host with intracellular bacteria expressing ovalbumin, (L.m.-ova), the donor (CD45.1+) transgenic, ova-specific T cells were found to generate many subsets of CD8+ T cells, including CD127+ memory T cells detected in spleen and lymph nodes. The figure, derived from fig. 1A, shows 2 host mice, one on each row; progeny of the transferred cell, the CD45.1+ population circled in the left panels, could be detected in about a quarter of the host mice. Progeny T cells were also detected in lungs. Both 'effector' and 'central' memory T cells (low vs. high CD62L) were detected, the former in the lymphoid organs and latter in the lungs. Upon restimulation of the progeny in vitro, production of the inflammatory cytokines interferon-gamma and tumor-necrosis-factor was detected, demonstrating maturation into effector T cells. This is a straightforward test, albeit technically demanding, that provides strong evidence that a single naïve T cell can generate many, and perhaps all, subsets.
Stemberger et al. Immunity. 2007 Dec 21;27(6):985-997. A Single Naive CD8(+) T Cell Precursor Can Develop into Diverse Effector and Memory Subsets.

How bacteria avoid dying alone

Programmed cell death, PCD or apoptosis, was discovered as the way individual cells altruistically remove themselves during development of a multi-cellular organism (e.g., C. elegans). However, single celled bacteria also undergo PCD to prevent the spread of a bacteriophage infection, for example. Stressed E. coli produce the stable endoribonuclease toxin MazF as well as the labile antitoxin MazE; even a transient interruption of protein synthesis can lead to PCD.

This group previously suggested that mazEF-mediated PCD depends on cell density. Here they show that indeed the mazEF system is only effective above ~3 million cells/ml. Adding supernatant from a dense culture to a diluted culture along with a stress-inducing antibiotic quickly induced PCD in wild-type (WT) cells but not cells in which mazEF is deleted (del-mazEF). This observation led them to identify an “extracellular death factor” (EDF) that is produced during log-phase growth but not during the stationary phase. Here they show that EDF is a pentapeptide (NNWNN) and that adding synthetic EDF to supernatants from stationary phase cultures renders them capable of inducing mazEF-induced PCD (Figure). High EDF (> 200 ng/ml) reduced viability of even del-mazEF strains, which the authors ascribe to perhaps inducing other PCD systems or inactivating essential components. Using mutagenesis, they demonstrated that NNWNN is the optimal sequence for EDF activity. No E. coli genes encode NNWNN but zwf-encoded NNWDN could be amidated to yield NNWNN and deletion of both zwf and ygeO, which encodes a similar NNWN peptide, prevented EDF induction. The authors propose a quorum-sensing role for EDF and point out that synthetic EDF “may be a lead for a new class of antibiotics that specifically trigger bacterial cell death".
Kolodkin-Gal et al. Science. 2007 Oct 26;318(5850):652-5. “A linear pentapeptide is a quorum-sensing factor required for mazEF-mediated cell death in Escherichia coli”.