The OX40 costimulatory receptor determines the development of CD4 memory by regulating primary clonal expansion.
The costimulatory receptor OX40 has recently been shown to be involved in primary CD4 responses to several defined Ags. However, to date there has been little information regarding the mechanism of action of OX40, such as whether it regulates T cell numbers, reactivity, or both, and whether it contributes to induction of long-term T cell responses. With an agonist Ab to OX40, and by tracking Ag-specific TCR transgenic T cells in vivo, we show that ligation of OX40 induces clonal expansion and survival of CD4 cells during primary responses, and results in the accumulation of greater numbers of memory cells with time. Significantly, OX40-deficient T cells, from mice generated by gene targeting, secrete IL-2 and proliferate normally during the initial period of activation, but cannot sustain this during the latter phases of the primary response, exhibiting decreased survival over time. Mice lacking OX40 develop only low frequencies of Ag-specific CD4 cells late in primary responses in vivo and generate dramatically lower frequencies of surviving memory cells. These results demonstrate that OX40-OX40L interactions control primary T cell expansion and the ability to retain high numbers of Ag-specific T cells. In this way, OX40 signals promote survival of greater numbers of T cells with time and control the size of the memory T cell pool.
Gramaglia
I
I
Division of Immunochemistry, La Jolla Institute for Allergy and Immunology, San Diego, CA 92121, USA.
Jember
A
A
Pippig
S D
SD
Weinberg
A D
AD
Killeen
N
N
Croft
M
M
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D002999:Clone Cells; D007106:Immune Sera / Q000494:pharmacology; D007156:Immunologic Memory / Q000235:genetics / Q000276:immunology*; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D018655:Lymphocyte Count; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011971:Receptors, Immunologic / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology*; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000235:genetics / Q000276:immunology / Q000502:physiology*
D007106:Immune Sera; D011971:Receptors, Immunologic; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor; C505717:Tnfrsf4 protein, mouse; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7