Peptide-specific killing of antigen-presenting cells by a recombinant antibody-toxin fusion protein targeted to major histocompatibility complex/peptide class I complexes with T cell receptor-like specificity

The mouse thymus contains a mature T cell subset that is distinguishable from the mainstream thymocytes by several characteristics. It is restricted in its usage of T cell receptor (TCR) V beta genes to V beta 8, V beta 7, and V beta 2. Its surface phenotype is that of activated/memory cells. It carries the natural killer NK1.1 surface marker. Furthermore, though it consists entirely of CD4+ and CD4-8- cells, its selection in the thymus depends solely upon major histocompatibility complex (MHC) class I expression by cells of hematopoietic origin. Forced persistence of CD8, in fact, imparts negative selection. Here, we have studied the TCR repertoire of this subset and found that, whereas the beta chain V-D-J junctions are quite variable, a single invariant alpha chain V alpha 14-J281 is used by a majority of the TCRs. This surprisingly restricted usage of the V alpha 14-J281 alpha chain is dependent on MHC class I expression, but independent of the MHC haplotype. In humans, a similar unusual population including CD4-8- cells can also be found that uses a strikingly homologous, invariant alpha chain V alpha 24-JQ. Thus, this unique V alpha-J alpha combination has been conserved in both species, conferring specificity to some shared nonpolymorphic MHC class I/peptide self-ligand(s). This implies that the T cell subset that it defines has a specialized and important role, perhaps related to its unique ability to secrete a large set of lymphokines including interleukin 4, upon primary stimulation in vitro and in vivo.

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Wild type and tailless CD8 display similar interaction with microfilaments during capping

Journal of Cell Science ◽

10.1242/jcs.100.2.329 ◽

1991 ◽

Vol 100 (2) ◽

pp. 329-337

Author(s):

P. Andre ◽

J. Gabert ◽

A.M. Benoliel ◽

C. Capo ◽

C. Boyer ◽

...

Keyword(s):

Major Histocompatibility Complex ◽

T Cell ◽

Cell Surface ◽

T Cell Receptor ◽

Cell Receptor ◽

Class I ◽

Surface Markers ◽

Major Histocompatibility ◽

Wild Type ◽

Histocompatibility Complex

We examined the influence of the intracytoplasmic region of CD8 alpha on capping and interaction with microfilaments. We used cell clones obtained by transfecting a CD4+ T-cell hybridoma with (a) T-cell receptor (TCR) alpha and beta chains from a cytolytic clone and (b) CD8 alpha genes that were either native or modified by extensive deletion of the intracytoplasmic region or replacement of the transmembrane and intracytoplasmic domains with those of a class I major histocompatibility complex gene (Letourneur et al. (1990). Proc. natn. Acad. Sci. U.S.A. 87, 2339–2343). Different cell surface structures were cross-linked with anti-T-cell receptor, anti-CD8 or anti-class I monoclonal antibodies and anti-immunoglobulin (Fab')2. Double labeling and quantitative image analysis were combined to monitor fluorescence anisotropy and correlation between different markers. Microfilaments displayed maximal polarization within two minutes. The correlation between these structures and surface markers was then maximal and started decreasing, whereas the redistribution of surface markers remained stable or continued. Furthermore, wild type and altered CD8 alpha exhibited similar ability to be capped and to induce co-capping of TCR and MHC (major histocompatibility complex) class I: the fraction of cell surface label redistributed into a localized cap ranged between 40% and 80%. Finally, cytochalasin D dramatically decreased CD8 capping in all tested clones. It is concluded that the transmembrane and/or intracellular domains of CD8 molecules are able to drive the extensive redistributions of membrane structures and cytoskeletal elements that are triggered by CD8 cross-linking.

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A Single T Cell Receptor Bound to Major Histocompatibility Complex Class I and Class II Glycoproteins Reveals Switchable TCR Conformers

Immunity ◽

10.1016/j.immuni.2011.04.017 ◽

2011 ◽

Vol 35 (1) ◽

pp. 23-33 ◽

Cited By ~ 51

Author(s):

Lei Yin ◽

Eric Huseby ◽

James Scott-Browne ◽

Kira Rubtsova ◽

Clamencia Pinilla ◽

...

Keyword(s):

Major Histocompatibility Complex ◽

T Cell ◽

Major Histocompatibility Complex Class ◽

T Cell Receptor ◽

Cell Receptor ◽

Class Ii ◽

Class I ◽

Complex Class ◽

Major Histocompatibility ◽

Histocompatibility Complex

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Clone-specific T cell receptor antagonists of major histocompatibility complex class I-restricted cytotoxic T cells.

Journal of Experimental Medicine ◽

10.1084/jem.177.6.1541 ◽

1993 ◽

Vol 177 (6) ◽

pp. 1541-1550 ◽

Cited By ~ 199

Author(s):

S C Jameson ◽

F R Carbone ◽

M J Bevan

Keyword(s):

T Cells ◽

Major Histocompatibility Complex ◽

T Cell ◽

T Cell Receptor ◽

Cell Receptor ◽

Class I ◽

Major Histocompatibility ◽

Class I Mhc ◽

Histocompatibility Complex ◽

T Cell Clone

A previous report showed that the proliferative response of helper T cells to class II major histocompatibility complex (MHC)-restricted antigens can be inhibited by analogues of the antigen, which act as T cell receptor (TCR) antagonists. Here we define and analyze peptide variants that antagonize various functions of class I MHC-restricted cytotoxic T lymphocyte (CTL) clones. Of 64 variants at individual TCR contact sites of the Kb-restricted octamer peptide ovalbumin257-264 (OVAp), a very high proportion (40%) antagonized lysis by three OVAp-specific CTL clones. This effect was highly clone specific, since many antagonists for one T cell clone have differential effects on another. We show that this inhibition of CTL function is not a result of T cell-T cell interaction, precluding veto-like phenomena as a mechanism for antagonism. Moreover, we present evidence for direct interaction between the TCR and antagonist-MHC complexes. In further analysis of the T cell response, we found that serine esterase release and cytokine production are susceptible to TCR antagonism similarly to lysis. Ca2+ flux, an early event in signaling, is also inhibited by antagonists but may be more resistant to the antagonist effect than downstream responses.

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T-Cell Receptor Usage of Major Histocompatibility Complex Class I Restricted Peptide-Specific T-Lymphocytes

Annals of the New York Academy of Sciences ◽

10.1111/j.1749-6632.1995.tb44478.x ◽

1995 ◽

Vol 756 (1 T-Cell Recept) ◽

pp. 12-18 ◽

Cited By ~ 5

Author(s):

U. C. GERTH ◽

P. A. H. MOSS ◽

J. I. BELL ◽

A. J. McMichael

Keyword(s):

Major Histocompatibility Complex ◽

T Cell ◽

T Lymphocytes ◽

Major Histocompatibility Complex Class ◽

T Cell Receptor ◽

Cell Receptor ◽

Class I ◽

Complex Class ◽

Major Histocompatibility ◽

Histocompatibility Complex

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The Final Maturation of at Least Some Single-Positive Cd4hiThymocytes Does Not Require T Cell Receptor–Major Histocompatibility Complex Contact

Journal of Experimental Medicine ◽

10.1084/jem.190.6.757 ◽

1999 ◽

Vol 190 (6) ◽

pp. 757-764 ◽

Cited By ~ 9

Author(s):

Ruben Dyall ◽

Janko Nikolić-Z̆ugić

Keyword(s):

Major Histocompatibility Complex ◽

T Cell ◽

T Cell Receptor ◽

Mhc Class Ii ◽

Cell Receptor ◽

Class Ii ◽

Class I ◽

Histocompatibility Complex ◽

Final Maturation ◽

Single Positive

The majority (∼70%) of postselection CD4+ single-positive (SP) thymocytes are CD8loCD4hi. These cells express very low levels of CD8, undetectable by flow cytofluorimetric (FCM) analysis, but sufficiently high to allow purification by panning. Unlike the fully mature CD8−CD4hi thymocytes, which account for the remaining ∼30% of the SP CD4+ thymocytes, CD8loCD4hi cells are functionally immature and short-lived unless they receive an unidentified maturation signal from the thymus. In this study, we tested the hypothesis that this signal is provided by a T cell receptor (TCR)–major histocompatibility complex (MHC) class II interaction. Using intrathymic transfer, we show that the immature CD8loCD4hi cells could complete their intrathymic maturation and populate the peripheral lymphoid organs in the absence of MHC class II (and class I) molecules. Furthermore, in mice devoid of class II (and class I) molecules, the progeny of CD8loCD4hi cells was long-lived and functionally reactive to allogeneic class II molecules, although their numbers in the spleen and the mesenteric lymph node were ∼40–50% lower than those in class II+ mice 5 mo after transfer. Control experiments demonstrated that the surviving cells did not originate from the contaminating mature thymocytes. These results demonstrate that the final maturation, proliferation, and peripheral survival (up to 5 mo) of at least some postselection CD4+ SP cells do not require the TCR–MHC class II interaction. They also indicate that the TCR–MHC class II interaction(s) required for the intrathymic development of long-lived CD4+ SP cells occurs before the CD4hi SP stage of development.

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The Energetic Basis Underpinning T-cell Receptor Recognition of a Super-bulged Peptide Bound to a Major Histocompatibility Complex Class I Molecule

Journal of Biological Chemistry ◽

10.1074/jbc.m112.344689 ◽

2012 ◽

Vol 287 (15) ◽

pp. 12267-12276 ◽

Cited By ~ 25

Author(s):

Yu Chih Liu ◽

Zhenjun Chen ◽

Scott R. Burrows ◽

Anthony W. Purcell ◽

James McCluskey ◽

...

Keyword(s):

Major Histocompatibility Complex ◽

T Cell ◽

Major Histocompatibility Complex Class ◽

T Cell Receptor ◽

Cell Receptor ◽

Class I ◽

Complex Class ◽

Mhc I ◽

Histocompatibility Complex ◽

Complementarity Determining Region

Although the major histocompatibility complex class I (MHC-I) molecules typically bind short peptide (p) fragments (8–10 amino acids in length), longer, “bulged” peptides are often be presented by MHC-I. Such bulged pMHC-I complexes represent challenges for T-cell receptor (TCR) ligation, although the general principles underscoring the interaction between TCRs and bulged pMHC-I complexes are unclear. To address this, we have explored the energetic basis of how an immunodominant TCR (termed SB27) binds to a 13-amino acid viral peptide (LPEPLPQGQLTAY) complexed to human leukocyte antigen (HLA) B*3508. Using the crystal structure of the SB27 TCR-HLA B*3508LPEP complex as a guide, we undertook a comprehensive alanine-scanning mutagenesis approach at the TCR-pMHC-I interface and examined the effect of the mutations by biophysical (affinity measurements) and cellular approaches (tetramer staining). Although the structural footprint on HLA B*3508 was small, the energetic footprint was even smaller in that only two HLA B*3508 residues were critical for the TCR interaction. Instead, the energetic basis of this TCR-pMHC-I interaction was attributed to peptide-mediated interactions in which the complementarity determining region 3α and germline-encoded complementarity determining region 1β loops of the SB27 TCR played the principal role. Our findings highlight the peptide-centricity of TCR ligation toward a bulged pMHC-I complex.

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