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Differential requirements of CD 4 + T ‐cell signals for effector cytotoxic T‐lymphocyte ( CTL ) priming and functional memory CTL development at higher CD 8 + T ‐cell precursor frequency
Author(s) -
Umeshappa Channakeshava S.,
Nanjundappa Roopa H.,
Xie Yufeng,
Freywald Andrew,
Xu Qingyong,
Xiang Jim
Publication year - 2013
Publication title -
immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.297
H-Index - 133
eISSN - 1365-2567
pISSN - 0019-2805
DOI - 10.1111/imm.12033
Subject(s) - ctl* , cytotoxic t cell , priming (agriculture) , cd8 , cd40 , biology , memory t cell , immunology , t cell , immune system , microbiology and biotechnology , biochemistry , botany , germination , in vitro
Summary Increased CD 8 + T ‐cell precursor frequency ( PF ) precludes the requirement of CD 4 + helper T ( T h) cells for primary CD 8 + cytotoxic T ‐lymphocyte ( CTL ) responses. However, the key questions of whether unhelped CTL s generated at higher PF are functional effectors, and whether unhelped CTL s can differentiate into functional memory cells at higher PF are unclear. In this study, ovalbumin ( OVA ) ‐pulsed dendritic cells ( DC OVA ) derived from C 57 BL /6, CD 40 knockout ( CD 40 −/− ) or CD 40 ligand knockout (CD40L −/− ) mice were used to immunize C 57 BL /6, I a b−/− , CD 40 −/− or CD 40 L −/− mice, whose PF was previously increased with transfer of 1 × 10 6 CD 8 + T cells derived from OVA ‐specific T ‐cell receptor ( TCR ) transgenic OTI , OTI ( CD 40 −/− ) or OTI ( CD 40L −/− ) mice. All the immunized mice were then assessed for effector and memory CTL responses. Following DC immunization, relatively comparable CTL priming occurred without CD 4 + T ‐cell help and T h‐provided CD 40/ CD 40 L signalling. In addition, the unhelped CTL s were functional effectors capable of inducing therapeutic immunity against established OVA ‐expressing tumours. In contrast, the functional memory development of CTL s was severely impaired in the absence of CD 4 + T ‐cell help and CD 40/ CD 40 L signalling. Finally, unhelped memory CTL s failed to protect mice against lethal tumour challenge. Taken together, these results demonstrate that CD 4 + T ‐cell help at higher PF , is not required for effector CTL priming, but is required for functional memory CTL development against cancer. Our data may impact the development of novel preventive and therapeutic approaches in cancer patients with compromised CD 4 + T ‐cell functions.