T cells in mice expressing a transgenic human TCR beta chain get positively selected but cannot be activated in the periphery by signaling through TCR.
TCR-CD3 complex-mediated signaling is crucial for both developmental selection and antigenic activation of T cells. We report that mice expressing a recombined human TCRbeta chain (Tg), which have normal development of T cells, mounted very weak responses to immunization with protein antigens as well as the HA307-319 peptide recognized by the human T cell clone HA1.7 from which the transgene is derived. An anti-CD3epsilon mAb triggered equivalent proliferation from Tg and non-Tg T cells, but an anti-human TCRbeta mAb induced proliferation poorly in Tg T cells in contrast to human T cells or HA1.7. In Tg mice, T cells expressing endogenous TCR were CD44(high), whereas most transgene-expressing T cells remained CD44(low), suggesting that transgene-expressing cells are not activated in the periphery to participate in immune responses. However, anti-human TCRbeta could induce some activation markers on T cells and cross-linking of the Tg TCR by plate-coated anti-human TCRbeta efficiently induced T cell proliferation. Human TCRbeta-mediated Tg T cell activation could be rescued by exogenous IL-2, as well as by the calcium ionophore A23187, but not by phorbol esters. Thus, this human TCRbeta chain functions efficiently for positive selection of mouse T cells, but not for their peripheral activation, probably because of a lack of oligomerization leading to defects in signaling for calcium flux and IL-2 induction. The data thus suggest an early point of separation of signaling pathways between positive selection and peripheral activation of T cells.
Pasare
C
C
National Institute of Immunology, Aruna Asaf Ali Road, New Delhi 110 067, India.
Mukherjee
P
P
Verhoef
A
A
Bansal
P
P
Mendiratta
S K
SK
George
A
A
Lamb
J R
JR
Rath
S
S
Bal
V
V
D000818:Animals; D000941:Antigens / Q000008:administration & dosage / Q000276:immunology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis; D015415:Biomarkers; D000001:Calcimycin / Q000494:pharmacology; D002478:Cells, Cultured; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology*; D019674:Genes, T-Cell Receptor beta / Q000235:genetics*; D006801:Humans; D007271:Injections, Intradermal; D007376:Interleukin-2 / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000235:genetics*; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D016853:Muromonab-CD3 / Q000494:pharmacology; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics* / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism*; D019076:Transgenes / Q000276:immunology*
D000941:Antigens; D000945:Antigens, Differentiation, T-Lymphocyte; D015415:Biomarkers; D007376:Interleukin-2; D007476:Ionophores; D016853:Muromonab-CD3; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D000001:Calcimycin; D010047:Ovalbumin