The Central Role of CD4+ T Cells in the Antitumor Immune Response

Abstract

The induction of optimal systemic antitumor immunity involves the priming of both CD4+ and CD8+ T cells specific for tumor-associated antigens. The role of CD4+ T helper cells (Th) in this response has been largely attributed to providing regulatory signals required for the priming of major histocompatibility complex class I restricted CD8+ cytolytic T lymphocytes, which are thought to serve as the dominant effector cell mediating tumor killing. However, analysis of the effector phase of tumor rejection induced by vaccination with irradiated tumor cells transduced to secrete granulocyte/macrophage colony-stimulating factor indicates a far broader role for CD4+ T cells in orchestrating the host response to tumor. This form of immunization leads to the simultaneous induction of Th1 and Th2 responses, both of which are required for maximal systemic antitumor immunity. Cytokines produced by these CD4+ T cells activate eosinophils as well as macrophages that produce both superoxide and nitric oxide. Both of these cell types then collaborate within the site of tumor challenge to cause its destruction.

IL‐7 is superior to IL‐2 for ex vivo expansion of tumour‐specific CD4+ T cells

“…In spite of the recognized importance of Ag-specific CD4 1 T cells in both adaptive and innate immune responses, their identification remains elusive, and their in vitro amplification is hindered by the absence of reliable protocols able to support cell proliferation in the absence of terminal differentiation. While, Ag tumours elicit natural tumour-specific CD4 1 T-cell responses [4][5][6][7][8][9][10], functional tolerance is eventually observed through the induction of T-cell anergy [11,12], T-cell depletion [13] or the limitation of the memory repertoire [10,14,15]. This is possibly due to Ag persistence, and continual TCR signaling, as in the case of chronic viral infections [16][17][18].…”

Steady‐state antigen‐expressing dendritic cells terminate CD4+ memory T‐cell responses

“…CD4 1 T cells, on the other hand, contribute to autoimmune and inflammatory diseases in a wide variety of ways. Effector CD4 1 T cells produce molecules that promote local inflammatory reactions or act to kill target cells either directly or by ''licensing'' intermediate cell types [8]. In addition to their direct effector functions, CD4 1 T cells also act as key regulators of adaptive immunity by, for instance, providing help to CD8 1 T cells and B cells.…”

CCL19 as an adjuvant for intradermal gene gun immunization in a Her2/neu mouse tumor model: improved vaccine efficacy and a role for B cells as APC

“…The latter point is indeed supported by a strong antiHer2/neu antibody response after gene gun immunization (but not after i.m. vaccination) and by depletion experiments in the same tumor model as well as in B16 melanoma showing that CD4 þ T cells play a pivotal role for tumor protection 27,42,43 Furthermore, it has previously been demonstrated in a Her2/neu þ tumor model, that multiple antigen-specific and non-specific immune mechanisms are responsible for tumor rejection, 44 (2) splenic T cells (which were used in our assays) do not sufficiently reflect systemic responses or responses at the tumor site and (3) T-cell assays used did not include the most relevant tumor rejection epitopes. Although our data show that Her2/neu vaccines are still immunogenic in B-cell-deficient mice, they also show that B cells are involved at least in mediating the adjuvant activity of CCL19.…”