naive T cell

**Definition and origin:** Naive T cells arise from thymocytes that have undergone positive selection (cortex; recognition of self-MHC on cortical epithelial cells) and negative selection (medulla; deletion of strongly self-reactive clones via AIRE-driven tissue-antigen presentation). They leave the thymus as single-positive CD4+ or CD8+ cells with a diverse TCR repertoire, but have never seen their specific antigen.

**Phenotype (high-yield markers):** CD45RA+ (memory cells switch to CD45RO), CCR7+, CD62L (L-selectin)+, CD27+, CD28+, CD3+, and either CD4+ or CD8+. They are small, resting (G0), with low activation markers (CD25-, CD69-) and low effector function.

**Trafficking:** CCR7 and CD62L let naive cells enter lymph nodes across high endothelial venules (HEVs), responding to CCL19/CCL21 in the T-cell zone (paracortex). They recirculate between blood and lymph nodes, spleen (periarteriolar lymphoid sheath, PALS), and Peyer's patches, surveying for antigen. Survival depends on IL-7 and tonic self-peptide:MHC signaling.

**Activation requirements:** - Signal 1: TCR binds peptide-MHC (CD4 with MHC II; CD8 with MHC I), transmitted via CD3. - Signal 2 (costimulation): CD28 on T cell binds B7 (CD80/86) on the APC. Without it, the cell becomes anergic. - Signal 3 (cytokines) drives differentiation. For CD4: IL-12 gives Th1; IL-4 gives Th2; TGF-β + IL-6 gives Th17; TGF-β + IL-2 gives Treg; IL-6/IL-21 gives Tfh. - Activation is mainly by mature dendritic cells, the most effective APC for naive T cells. Macrophages and B cells primarily activate previously primed cells. - IL-2 (autocrine) drives clonal expansion.

**Fate after activation:** Effector T cells (CD45RO+, CD62L lost in effector subsets, which migrate to peripheral tissues) and memory T cells (central memory CCR7+/CD62L+; effector memory CCR7-). Contraction follows antigen clearance.

**Clinical significance:** - DiGeorge syndrome (22q11 deletion): thymic aplasia causes few naive T cells, with low TREC levels, hypocalcemia, and conotruncal defects. - SCID: absent or markedly reduced naive T cells. Newborn screening uses TRECs (T-cell receptor excision circles), which are markers of recent thymic emigrants. - HIV: CD4 depletion with progressive loss of naive CD4+ cells and immune exhaustion. CCR5/CXCR4 are coreceptors. - Aging: thymic involution reduces the naive T-cell output, shrinking the repertoire and impairing responses to novel antigens and vaccines. - Immune checkpoint and costimulation therapies: abatacept (CTLA-4-Ig) blocks CD28-B7 costimulation, preventing naive T-cell activation (used in RA, transplant: belatacept). Anti-CTLA-4 (ipilimumab) enhances priming. - Anergy and tolerance: TCR signaling without costimulation leads to anergy, a mechanism of peripheral tolerance. - Flow cytometry: the CD45RA+/CCR7+ combination identifies naive cells; CD45RO+ identifies memory cells.

**Board pearls:** Naive T cells are activated in secondary lymphoid organs (not in peripheral tissue), need costimulation (B7:CD28), and are the cell type most dependent on dendritic cells. The primary response (naive) is slower and smaller than the secondary (memory) response.