Absence of CD4+ T cell help generates corrupt CD8+ effector T cells in sarcoma-bearing Swiss mice treated with NLGP vaccine

• NLGP mediated therapeutic tumor growth restriction is CD8+ T cell dependent.
• In this CD8 dependent tumor growth restriction participation of CD4+ T cells is essential.
• CD4+ T cell depletion increases CD8+ T cell frequency in tumor bearing mice, however, CD8+ T cell functions are seriously hampered.
• CD4+ T cell depletion affects NLGP vaccine induced CD8α+ dendritic cell dependent signaling.
• IL-2 and physical presence of CD4+ T cells are mutually required for optimum CD8+ T cell functions.

One of the prime objectives of cancer immunology and immunotherapy is to study the issues related to rescue and/or maintenance of the optimum effector CD8+ T cell functions by minimizing tumor-induced negative factors. In this regard the influence of host intrinsic CD4+ helper T cells towards generation and maintenance of CD8+ effector T cells appears controversial in different experimental settings. Therefore, the present study was aimed to re-analyze the influence of CD4+ helper T cells towards effector T cells during neem leaf glycoprotein (NLGP)-vaccine-mediated tumor growth restriction. CD4 depletion (mAb; Clone GK1.5) surprisingly resulted in significant increase in CD8+ T cells in different immune organs from NLGP-treated sarcoma-bearing mice. However, such CD8 surge could not restrict the sarcoma growth in NLGP-treated CD4-depleted mice. Furthermore, CD4 depletion in early phase hinders CD8+ T cell activation and terminal differentiation by targeting crucial transcription factor Runx3. CD4 depletion decreases accumulation of CD8α+ dendritic cells within tumor draining lymph node, hampers antigen cross priming and CD86-CD28 interactions for optimum CD8+ T cell functions. In order to search the mechanism of CD4+ T cell help on NLGP-mediated CD8 effector functions, the role of CD4+ helper T cell-derived IL-2 on optimization of CD8 functions was found using STAT5 signaling, but complete response requires physical contact of CD4+ helper T cells with its CD8 counterpart. In conclusion, it was found that CD4+ T cell help is not required to generate CD8+ T cells but was found to be an integral phenomenon in maintenance of its anti-tumor functions even in NLGP-vaccine-mediated sarcoma growth restriction.